Niacin Mimetics, and Methods of Use Thereof

ABSTRACT

Disclosed are 6-(morpholinoalkyl)-substituted pyridines, and pharmaceutically acceptable salts and prodrugs thereof, that are active against a range of mammalian therapeutic indications.

RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.13/168,616, filed Jun. 24, 2011, which claims the benefit of priority toU.S. Provisional Patent Application Ser. No. 61/358,264, filed Jun. 24,2010, the contents of which are hereby incorporated by reference.

BACKGROUND

Hyperlipidemia and hypercholesterolemia are conditions that have a wellestablished correlation with increased risk of other conditions, such asheart attacks, atherosclerosis, and other deleterious ailments. Thereare numerous agents available for lowering cholesterol and lipid levels,including gemfibrizol, probucol, and, more recently, the “statins”(e.g., lovastatin).

Niacin (nicotinic acid), a water soluble B-complex vitamin, is usedorally for the treatment of hyperlipidemia. Niacin has been shown to beeffective in reducing total plasma cholesterol (C), low-densitylipoproteins LDL-C and very low density lipoprotein triglycerides(VLDL-triglycerides), all of which are associated with health risks.Simultaneously, niacin raises serum levels of high density lipoproteins(HDL-C), which are considered a “healthy” lipoprotein, in patients withtypes II, III, IV, and V hyperlipoproteinemia.

Although the mechanism by which niacin alters lipid profiles has notbeen well defined, its mechanisms of action have been shown to includeinhibition of free fatty acid release from adipose tissue (see Carlson,L. A., Froberg, S. O. and Nye, E. R., Nicotinic acid in the rat. 11.Acute effects of nicotinic acid on plasma, liver, heart, and musclelipids, Acta Med Scand 180: 571-579, 1966), and increased lipoproteinlipase activity (see Priego, J. G., Pina, M., Armijo, M., Sunkel, C. andMaroto, M. L., Action of etofibrate, clofibrate and nicotinic acid onthe metabolism of lipids in normolipemic rats. Short term effects andmethod of action, Arch Farmacol Toxicol 5: 29-42, 1979). More than 30million Americans have elevated blood LDL-C levels. HMG-CoA reductaseinhibitors (statins) are the most widely used class of drugs fortreating patients with elevated levels of LDL-C. Niacin, however, is theonly drug recommended by the American Heart Association for HDLimprovement in primary prevention of cardiovascular diseases in additionto lowering LDL-C. Niacin therapy is not only cost-effective as amonotherapy, but it is also beneficial as a combination therapy becauseit complements the effects of other classes of lipid-lowering drugs.However, niacin is a second or third choice for isolatedhypercholesterolemia because of a high incidence of side effectsassociated with oral niacin therapy. Nevertheless, it has a therapeuticadvantage as a monotherapy when reduction of both LDL-C andtriglycerides are desired, such as for patients with severe combinedhyperlipidemia.

Niacin may also be used in combination with other cholesterol-loweringagents, such as the “statins”, to maximize lipid-lowering activity. Onestudy showed that a niacin/lovastatin combination is highly effective inlowering LDL-C, triglycerides and lipoprotein (a) (Lp(a)) whileretaining niacin's potency in raising HDL-C (Kashyap, M. L., Evans R.,Simmons, P. D., Kohler, R. M. and McGoven, M. E., New combinationniacin/statin formulation shows pronounced effects on major lipoproteinsand well tolerated, J Am Coll Card Suppl. A 35: 326, 2000).

Niacin has been widely used for reducing serum cholesterol levelsbecause it is considered a cost-effective therapy. Daily oral doses of2-3 g niacin in humans reduce levels of total-C and LDL-C by an averageof 20% to 30%, reduce triglyceride levels 35% to 55%, increase HDL-C 20%to 35%, and reduce Lp(a). Niacin also reduces total mortality as well asmortality from coronary artery disease (see The Coronary Drug ProjectResearch Group, JAMA 231: 360-381, 1975; and Canner, P. L., Berge, K.G., Wenger, N. K., Stamler, J., Friedman, L., Prineas, R. J. andFriedewald, W., Fifteen year mortality in Coronary Drug Projectpatients: long-term benefit with niacin, J Am Coll Cardiol 8: 1245-1255,1986) and it helps to slow or reverse the progression of atherosclerosis(see Blankenhorn, D. H., Nessim, S. A., Johnson, R. L., Samnarco, M. E.,Azen, S. P. and Cashin-Hemphill, L., Beneficial effects of combinedcolestipol-niacin therapy on coronary atherosclerosis and coronaryvenous bypass grafts, JAMA 257: 3233-3240, 1987; and Cashin-Hemphill L.;Mack, W. J., Pogoda, J. M., Samnarco, M. E., Azen, S. P. andBlankenhorn, D. H., Beneficial effects of colestipol-niacin on coronaryatherosclerosis. A 4-year follow-up, JAMA 264: 3013-3017, 1990).

Unfortunately, oral niacin therapy has side effects that limit itsutility. Although niacin is a vitamin, it must be used in therapeuticdoses to lower cholesterol. At these doses, both immediate-release andsustained-release niacin can have several side effects. The most commonside effect of niacin is flushing, a warm feeling in the skin usuallyassociated with redness and sometimes itching. Flushing is notdangerous, but most patients find it very uncomfortable, which seriouslylimits patient compliance with niacin therapy. Niacin-induced flushingcan be substantially attenuated by pretreatment with cyclooxygenaseinhibitors, suggesting that the vasodilation is caused by aprostaglandin-mediated mechanism (see Carlson, L. A., Nicotinic acid andinhibition of fat mobilizing lipolysis. Present status, of effects onlipid metabolism, Adv Exp Med Biol 109: 225-23 8, 1978).

Liver function tests are always monitored in patients taking niacinsince elevation of serum transaminase levels has been associated withniacin treatment, and sustained-release niacin formulations have beenassociated with more serious liver problems (see McKenney, J. M.,Proctor, J. D., Harris, S., and Chinchili, V. M., A comparison of theefficacy and toxic effects of sustained- vs immediate-release niacin inhypercholesterolemic patients, JAMA 271: 672-777, 1994; and Stafford, R.S., Blumenthal, D. and Pasternak, R. C., Variations in cholesterolmanagement practices of U.S. physicians, J Am Coll Cardiol 29: 139-146,1997). Other known side effects of oral niacin therapy includeactivation of peptic ulcers, gout, and worsening of diabetes control.Accordingly, the safety and efficacy of oral niacin therapy isundermined by the need for careful clinical monitoring and thecompound's side-effect profile.

SUMMARY

One aspect of the present invention relates to6-(morpholinoalkyl)-substituted pyridines, and pharmaceuticallyacceptable salts thereof, that are active against a range of mammalianmaladies. In certain embodiments, said pyridines or salts thereofcomprise a functional group that is substantially anionic atphysiological pH.

Another aspect of the invention relates to a pharmaceutical composition,comprising a compound of the present invention or a pharmaceuticallyacceptable salt thereof; and a pharmaceutically acceptable excipient.Yet another aspect of the invention relates to a pharmaceuticalcomposition, comprising a compound of the present invention or apharmaceutically acceptable salt thereof; niacin; and a pharmaceuticallyacceptable excipient.

Another aspect of the invention relates to a pharmaceutical composition,comprising a compound of the present invention or a pharmaceuticallyacceptable salt thereof; a statin selected from the group consisting ofatorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,pitavastatin, pravastatin, rosuvastatin and simvastatin; and apharmaceutically acceptable excipient. The present invention alsorelates to a pharmaceutical composition, comprising a compound of thepresent invention or a pharmaceutically acceptable salt thereof; niacin;a statin selected from the group consisting of atorvastatin,cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin,pravastatin, rosuvastatin and simvastatin; and a pharmaceuticallyacceptable excipient. Additional therapeutic agents which can beco-administered with compounds of the invention are discussed below.

Niacin, or nicotinic acid, has established efficacy for the treatment ofdyslipidemia, but the clinical use of niacin has been limited bycutaneous flushing, a well-recognized associated adverse effect.Flushing, which is estimated at a prevalence as high as 25% to 40%, hasbeen cited as the major reason for the discontinuation of niacintherapy. A number of studies have established that moderate doses ofprostaglandin inhibitors reduce the cutaneous flushing response fromniacin administration. Other strategies for reducing flushing includeregular consistent dosing, the use of extended-release formulations,patient education, dosing with meals or at bedtime, and the avoidance ofalcohol, hot beverages, spicy foods, and hot baths or showers close toor after dosing. In certain embodiments, compounds of the presentinvention can have reduced occurrence or severity of flushing whenadministered to an animal, particularly a human patient.

For instance, compounds of the present invention do not cause flushingin the male C57BL/6 murine model of flushing, as measured by laserDoppler flowmetry, when administered at doses of up to 100 mg/kg, andeven more preferably when administered at doses up to 200, 300, or even500 mg/kg.

In certain embodiments, compounds of the present invention can becharacterized by causing less flushing when administered orally whencompared to the amount equivalent molar amount of NIASPAN® (niacinextended-release tablets, Abbott Laboratories). In certain embodiments,compounds of the present invention when administered orally to anaverage patient population, shows a reduction in the number of patientsreporting flushing of greater than or equal to 5 on the visual analogscale orally when compared to the equivalent molar amount of NIASPAN®.

The present invention also relates to a method of treating a disease,disorder, or condition selected from the group consisting ofhyperlipidemia, hypercholesterolemia, lipodystrophy, dyslipidemia,atherosclerosis, and coronary artery disease, comprising the step ofadministering to a mammal in need thereof a therapeutically effectiveamount of a compound or pharmaceutical composition of the presentinvention.

Another aspect of the present invention relates to a method of treatinga disease, disorder, or condition selected from the group consisting ofmetabolic syndrome, obesity, fatty liver disease, and diabetes,comprising the step of administering to a mammal in need thereof atherapeutically effective amount of a compound or pharmaceuticalcomposition of the present invention.

Another aspect of the present invention relates to a method of raisingserum high-density lipoprotein (HDL) levels, comprising the step of:administering to a mammal in need thereof a therapeutically effectiveamount of a compound or pharmaceutical composition of the presentinvention.

Another aspect of the present invention relates to a method of loweringserum low-density lipoprotein (LDL) levels or lowering serum lipoprotein(a) levels, comprising the step of administering to a mammal in needthereof a therapeutically effective amount of a compound orpharmaceutical composition of the present invention.

Another aspect of the present invention relates to a method ofincreasing the serum total concentrations of adiponectin, comprising thestep of administering to a mammal in need thereof a therapeuticallyeffective amount of a compound or pharmaceutical composition of thepresent invention.

Another aspect of the present invention relates to a method of treatinga disease, disorder, or condition selected from the group consisting ofcongestive heart failure, cardiovascular disease, hypertension, coronaryheart disease, angina, pellagra, Hartnup's syndrome, carcinoid syndrome,arterial occlusive disease, hypothyroidism, vasoconstriction,osteoarthritis, rheumatoid arthritis, Alzheimer's disease, disorders ofthe peripheral and central nervous system, hematological diseases,cancer, inflammation, respiratory diseases, and gastroenterologicaldiseases, comprising the step of administering to a mammal in needthereof a therapeutically effective amount of a compound orpharmaceutical composition of the present invention.

Additional aspects, embodiments, and advantages of the invention arediscussed below in detail.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Liquid chromatography-mass spectroscopy (LC-MS) trace forART-001 received from Shanghai SpeedChem (Shanghai, China). UVabsorption at 215 nm was used to determine purity. The area of the peakat 3.59 min represents 98.9% of the total peak area of the trace.

FIG. 2. Relative stability of ARI-001 under storage conditions asdefined in the text. Total area representing the peak for ART-001 wascalculated and then normalized to the total area of peaks identified onthe LC-MS trace. This is expressed as % of total peaks.

Upper graph, powder formulation; (▪) standard conditions: 50° C., nospecified humidity. Lower graph, liquid formulation; (⋄) roomtemperature (rt); (▪) 4° C.; (▴) 20° C.

FIG. 3. Overlaid FPLC traces of pooled plasma from hamsters on either anormal chow diet (solid line) or a high fat+high sugar (HF/HS) diet(dotted line).

FIG. 4. FPLC traces of pooled plasma from hamsters receiving vehicle(solid line), 1200 mg/kg (mpk) niacin (dotted line), or 2240 mg/kgART-001 (dashed line).

FIG. 5. Lipid parameter changes as a function of dose of ARI-001(represented in mmol/kg/d). ART-001 (▪ and connecting line) demonstratesa dose-dependent effect on lipid values in HF/HS hamsters. Niacin (⋄)showed significance with respect to changes in total cholesterol (TC),high-density lipoporotein (HDL), and low-density lipoprotein (LDL) only.

FIGS. 6 and 7. Correlation between lipid parameters and plasmaconcentrations of ARI-001. Each lipid parameter achieved statisticallysignificant negative correlations with ART-001 concentrations, exceptfor HDL, which was statistically significant and positive. The linearcorrelation line is drawn (solid line), as well as the 95% confidencezone of the correlation line (dashed curves). Pearson r correlationcoefficients are given for each data set, with 95% confidence intervalin parentheses. P-values are the results of 2-tailed unpaired t-tests.

FIG. 8. (Left graph) Correlation between liver and plasma concentrationsof ARI-001 in HF/HS hamsters dosed for 18 days. The values for eachtissue have been transformed by logarithm, and therefore, the axes areunitless. (Right graph) Correlation between adipose and plasmaconcentrations in the same animals. Adipose concentrations have beentransformed by the function “logarithm +1”, which makes any valuesbetween −1 and 0 into positive values. This is done for clarity and doesnot otherwise distort the distribution of the data set.

FIGS. 9-11. Correlations between liver concentrations of ARI-001 inHF/HS hamsters and values of different lipid parameters; also,correlations between adipose tissue concentrations of ARI-001 in HF/HShamsters and values of different lipid parameters. All values are thelogarithm of the lipid values versus the logarithm of the tissueconcentrations. Correlations are between tissue concentration and lipidvalues in the same animals. Adipose concentrations have been transformedby the function “logarithm +1”, which makes any values between −1 and 0into positive values. This is done for clarity and does not otherwisedistort the distribution of the data set.

FIGS. 12A and B. Liver function test parameters from high fat-fedhamsters dosed orally with vehicle, niacin, or ARI-001 for 18 days.Percent changes are given relative to vehicle. P-values are reportedfrom 2-tailed unpaired t-tests comparing to vehicle. FIG. 12A, aspartateaminotransferase (AST). FIG. 12B, alanine aminotransferase (ALT).

FIG. 13. Glucose values measured in plasma from an 18 day study of HF/HShamsters dosed daily with vehicle, niacin, or ARI-001. Percent changesare reported in comparison to the vehicle group values. P-value isdetermined from a 2-tailed t-test.

FIG. 14. Plasma concentrations of ARI-001 from mice dosed with a singleadministration of ARI-001 either orally (PO) or intraperitoneally (IP).

FIGS. 15A-15D. Plasma concentrations of ARI-001 from mice dosed withmultiple daily oral administrations of ARI-001 for 30 consecutive days.Four different doses were used. Each mouse received the same indicateddose of ARI-001 every day for 30 days.

FIGS. 16A and 16B. Summary of C_(max) and AUC parameters for ARI-001from 30-day multiple administration study in wild type mice. Values areplotted as the mean with standard error. There was no significant changein either parameter as a function of time. (◯) 996 mg/kg/d; (□) 1493mg/kg/d; (Δ) 2240 mg/kg/d; (⋄) 3360 mg/kg/d.

FIG. 17. Plasma concentrations of ARI-001 in Golden Syrian Hamsters onhigh fat/high sugar diet after single administration of ARI-001 at 5.9mmol/kg.

FIG. 18. Plasma concentrations of ARI-001 in fasted monkeys after singleadministration of ARI-001 either (♦) 96 mg/kg intravenously (IV) or (◯)288 mg/kg (mpk) orally (PO). Y-axis is logarithmic scale for clarity.(Inset): Same data, with the y-axis on a linear scale.

FIG. 19. Plasma concentrations of ARI-001 after single administration of288 mg/kg orally to (♦) fed monkeys or to (◯) fasted monkeys. Values aremean with standard error.

FIG. 20. Plasma concentrations of ARI-001 after repeated dailyadministration of 288 mg/kg orally to fasted monkeys. Values are meanwith standard error. (♦) Samples drawn on day 1. (◯) Samples drawn onday 7.

FIG. 21. ARI-001 fails to recruit beta-arrestin to the cell membrane ofcells expressing the niacin receptor GPR109A. Ligand refers to niacin orARI-001, as indicated. RLU, relative light units, as measured inchemiluminescent read-out for G protein-coupled receptor activity.

FIG. 22. Dose response for triglyceride lowering on single oral doses ofARI-001 to human patients. The percent change is the mean percent changein triglycerides at 4 hours post dose.

FIG. 23. Serum concentration of ARI-001 over time following single oraladministration of indicated amounts of ARI-001 to human patients.

DETAILED DESCRIPTION

One aspect of the invention relates to niacin analogs for use in raisingserum HDL levels in mammals. In certain embodiments, the compounds ofthe invention have equal or greater HDL-raising ability than niacinwhile having less or no propensity to induce flushing, an undesirableside effect of niacin itself when used in doses sufficient to raiseserum HDL levels. Some non-flushing niacin analogs are described in U.S.Patent Application Publication No. 2009/0312355, which is herebyincorporated by reference in its entirety. In certain embodiments, keystructural features of the compounds disclosed herein appear to includethe placement of a heterocyclylalkyl or heteroaralkyl group para to thecarboxyl group in niacin.

DEFINITIONS

For convenience, certain terms employed in the specification, examples,and appended claims are collected here. All definitions, as defined andused herein, supersede dictionary definitions, definitions in documentsincorporated by reference, and/or ordinary meanings of the definedterms.

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Multiple elements listed with“and/or” should be construed in the same fashion, i.e., “one or more” ofthe elements so conjoined. Other elements may optionally be presentother than the elements specifically identified by the “and/or” clause,whether related or unrelated to those elements specifically identified.Thus, as a non-limiting example, a reference to “A and/or B”, when usedin conjunction with open-ended language such as “comprising” can refer,in one embodiment, to A only (optionally including elements other thanB); in another embodiment, to B only (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (i.e., “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of” “Consisting essentially of,” when used in the claims,shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from any one or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

It should also be understood that, unless clearly indicated to thecontrary, in any methods claimed herein that include more than one stepor act, the order of the steps or acts of the method is not necessarilylimited to the order in which the steps or acts of the method arerecited.

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” “composed of,” and the like are tobe understood to be open-ended, i.e., to mean including but not limitedto. Only the transitional phrases “consisting of” and “consistingessentially of” shall be closed or semi-closed transitional phrases,respectively, as set forth in the United States Patent Office Manual ofPatent Examining Procedures, Section 2111.03.

The terms “co-administration” and “co-administering” refer to bothconcurrent administration (administration of two or more therapeuticagents at the same time) and time varied administration (administrationof one or more therapeutic agents at a time different from that of theadministration of an additional therapeutic agent or agents), as long asthe therapeutic agents are present in the patient to some extent at thesame time.

The term “solvate” refers to a pharmaceutically acceptable form of aspecified compound, with one or more solvent molecules, that retains thebiological effectiveness of such compound. Examples of solvates includecompounds of the invention in combination with solvents such, forexample, water (to form the hydrate), isopropanol, ethanol, methanol,dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, oracetone. Also included are formulations of solvate mixtures such as acompound of the invention in combination with two or more solvents.

The definition of each expression, e.g., alkyl, m, n, and the like, whenit occurs more than once in any structure, is intended to be independentof its definition elsewhere in the same structure.

It will be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance withpermitted valence of the substituted atom and the substituent, and thatthe substitution results in a stable compound, e.g., a compound whichdoes not spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction.

The term “substituted” is also contemplated to include all permissiblesubstituents of organic compounds. In a broad aspect, the permissiblesubstituents include acyclic and cyclic, branched and unbranched,carbocyclic and heterocyclic, aromatic and nonaromatic substituents oforganic compounds. Illustrative substituents include, for example, thosedescribed herein below. The permissible substituents may be one or moreand the same or different for appropriate organic compounds. Forpurposes of this invention, the heteroatoms such as nitrogen may havehydrogen substituents and/or any permissible substituents of organiccompounds described herein which satisfy the valences of theheteroatoms.

The term “lower” when appended to any of the groups listed belowindicates that the group contains less than seven carbons (i.e., sixcarbons or less). For example “lower alkyl” refers to an alkyl groupcontaining 1-6 carbons, and “lower alkenyl” refers to an alkyenyl groupcontaining 2-6 carbons.

The term “unsaturated,” as used herein, pertains to compounds and/orgroups which have at least one carbon-carbon double bond orcarbon-carbon triple bond.

The term “aliphatic,” as used herein, pertains to compounds and/orgroups which are linear or branched, but not cyclic (also known as“acyclic” or “open-chain” groups).

The term “cyclic,” as used herein, pertains to compounds and/or groupswhich have one ring, or two or more rings (e.g., spiro, fused, bridged).“Monocyclic” refers to compounds and/or groups with one ring; and“bicyclic” refers to compouinds/and or groups with two rings.

The term “aromatic” refers to a planar or polycyclic structurecharacterized by a cyclically conjugated molecular moiety containing4n+2 electrons, wherein n is the absolute value of an integer. Aromaticmolecules containing fused, or joined, rings also are referred to asbicyclic aromatic rings. For example, bicyclic aromatic rings containingheteroatoms in a hydrocarbon ring structure are referred to as bicyclicheteroaryl rings.

The term “hydrocarbon” as used herein refers to an organic compoundconsisting entirely of hydrogen and carbon.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

The term “heteroatom” as used herein is art-recognized and refers to anatom of any element other than carbon or hydrogen. Illustrativeheteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur andselenium.

The term “alkyl” means an aliphatic or cyclic hydrocarbon radicalcontaining from 1 to 20, 1 to 15, or 1 to 10 carbon atoms.Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,2-methylcyclopentyl, 1-(1-ethylcyclopropyl)ethyl and 1-cyclohexylethyl.

The term “cycloalkyl” is a subset of alkyl which refers to cyclichydrocarbon radical containing from 3 to 15, 3 to 10, or 3 to 7 carbonatoms. Representative examples of cycloalkyl include, but are notlimited to, cyclopropyl and cyclobutyl.

The term “alkenyl” as used herein means a straight or branched chainhydrocarbon radical containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond formed by the removal of twohydrogens. Representative examples of alkenyl include, but are notlimited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkynyl” as used herein means a straight or branched chainhydrocarbon radical containing from 2 to 10 carbon atoms and containingat least one carbon-carbon triple bond. Representative examples ofalkynyl include, but are not limited, to acetylenyl, 1-propynyl,2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term “alkylene,” is art-recognized, and as used herein pertains to adiradical obtained by removing two hydrogen atoms of an alkyl group, asdefined above.

The term “carbocyclyl” as used herein means a monocyclic or multicyclic(e.g., bicyclic, tricyclic, etc.) hydrocarbon radical containing from 3to 12 carbon atoms that is completely saturated or has one or moreunsaturated bonds, and for the avoidance of doubt, the degree ofunsaturation does not result in an aromatic ring system (e.g., phenyl).Examples of carbocyclyl groups include 1-cyclopropyl, 1-cyclobutyl,2-cyclopentyl, 1-cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl and2-cyclopentenylmethyl.

The term “heterocyclyl”, as used herein refers to a radical of anon-aromatic, ring system, including, but not limited to, monocyclic,bicyclic and tricyclic rings, which can be completely saturated or whichcan contain one or more units of unsaturation, for the avoidance ofdoubt, the degree of unsaturation does not result in an aromatic ringsystem, and have 3 to 12 atoms including at least one heteroatom, suchas nitrogen, oxygen, or sulfur. For purposes of exemplification, whichshould not be construed as limiting the scope of this invention, thefollowing are examples of heterocyclic rings: aziridinyl, azirinyl,oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, azetyl,oxetanyl, oxetyl, thietanyl, thietyl, diazetidinyl, dioxetanyl,dioxetenyl, dithietanyl, dithietyl, furyl, dioxalanyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,triazinyl, isothiazolyl, isoxazolyl, thiophenyl, pyrazolyl, tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl,quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pyridopyrazinyl,benzoxazolyl, benzothiophenyl, benzimidazolyl, benzothiazolyl,benzoxadiazolyl, benzthiadiazolyl, indolyl, benztriazolyl,naphthyridinyl, azepines, azetidinyl, morpholinyl, oxopiperidinyl,oxopyrrolidinyl, piperazinyl, piperidinyl, pyrrolidinyl, quinicludinyl,thiomorpholinyl, tetrahydropyranyl and tetrahydrofuranyl. Theheterocyclyl groups of the invention are substituted with 0, 1, 2, 3, 4or 5 substituents independently selected from the group consisting ofalkyl, alkenyl, alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy,alkyenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy, haloalkoxy,fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio,alkyenylthio, alkynylthio, sulfonic acid, alkylsulfonyl,haloalkylsulfonyl, fluoroalkylsulfonyl, alkenylsulfonyl,alkynylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl,fluoroalkoxysulfonyl, alkenyloxysulfonyl, alkynyloxysulfony,aminosulfonyl, sulfinic acid, alkylsulfinyl, haloalkylsulfinyl,fluoroalkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkoxysulfinyl,haloalkoxysulfinyl, fluoroalkoxysulfinyl, alkenyloxysulfinyl,alkynyloxysulfiny, aminosulfinyl, formyl, alkylcarbonyl,haloalkylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl,alkynylcarbonyl, carboxyl, alkoxycarbonyl, haloalkoxycarbonyl,fluoroalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,alkylcarbonyloxy, haloalkylcarbonyloxy, fluoroalkylcarbonyloxy,alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy,haloalkylsulfonyloxy, fluoroalkylsulfonyloxy, alkenylsulfonyloxy,alkynylsulfonyloxy, haloalkoxysulfonyloxy, fluoroalkoxysulfonyloxy,alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy,haloalkylsulfinyloxy, fluoroalkylsulfinyloxy, alkenylsulfinyloxy,alkynylsulfinyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy,fluoroalkoxysulfinyloxy, alkenyloxysulfinyloxy, alkynyloxysulfinyloxy,aminosulfinyloxy, amino, amido, aminosulfonyl, aminosulfinyl, cyano,nitro, azido, phosphinyl, phosphoryl, silyl, silyloxy, and any of saidsubstiuents bound to the heterocyclyl group through an alkylene moiety(e.g., methylene).

The term “aryl,” as used herein means a phenyl, naphthyl, phenanthrenyl,or anthracenyl group. The aryl groups of the present invention can beoptionally substituted with 1, 2, 3, 4 or 5 substituents independentlyselected from the group consisting of alkyl, alkenyl, alkynyl, halo,haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkyenyloxy, alkynyloxy,carbocyclyloxy, heterocyclyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl,alkylthio, haloalkylthio, fluoroalkylthio, alkyenylthio, alkynylthio,sulfonic acid, alkylsulfonyl, haloalkylsulfonyl, fluoroalkylsulfonyl,alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl,fluoroalkoxysulfonyl, alkenyloxysulfonyl, alkynyloxysulfony,aminosulfonyl, sulfinic acid, alkylsulfinyl, haloalkylsulfinyl,fluoroalkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkoxysulfinyl,haloalkoxysulfinyl, fluoroalkoxysulfinyl, alkenyloxysulfinyl,alkynyloxysulfiny, aminosulfinyl, formyl, alkylcarbonyl,haloalkylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl,alkynylcarbonyl, carboxyl, alkoxycarbonyl, haloalkoxycarbonyl,fluoroalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,alkylcarbonyloxy, haloalkylcarbonyloxy, fluoroalkylcarbonyloxy,alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy,haloalkylsulfonyloxy, fluoroalkylsulfonyloxy, alkenylsulfonyloxy,alkynylsulfonyloxy, haloalkoxysulfonyloxy, fluoroalkoxysulfonyloxy,alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy,haloalkylsulfinyloxy, fluoroalkylsulfinyloxy, alkenylsulfinyloxy,alkynylsulfinyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy,fluoroalkoxysulfinyloxy, alkenyloxysulfinyloxy, alkynyloxysulfinyloxy,aminosulfinyloxy, amino, amido, aminosulfonyl, aminosulfinyl, cyano,nitro, azido, phosphinyl, phosphoryl, silyl, silyloxy, and any of saidsubstiuents bound to the heterocyclyl group through an alkylene moiety(e.g., methylene).

The term “arylene,” is art-recognized, and as used herein pertains to adiradical obtained by removing two hydrogen atoms of an aryl ring, asdefined above.

The term “arylalkyl” or “aralkyl” as used herein means an aryl group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein.

Representative examples of aralkyl include, but are not limited to,benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.

The term “biaryl,” as used herein means an aryl-substituted aryl, anaryl-substituted heteroaryl, a heteroaryl-substituted aryl or aheteroaryl-substituted heteroaryl, wherein aryl and heteroaryl are asdefined herein. Representative examples include 4-(phenyl)phenyl and4-(4-methoxyphenyl)pyridinyl.

The term “heteroaryl” as used herein include radicals of aromatic ringsystems, including, but not limited to, monocyclic, bicyclic andtricyclic rings, which have 3 to 12 atoms including at least oneheteroatom, such as nitrogen, oxygen, or sulfur. For purposes ofexemplification, which should not be construed as limiting the scope ofthis invention: aminobenzimidazole, benzimidazole, azaindolyl,benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl,benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl,furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl,isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl,oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl,pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl,pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl,thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl,thienyl, thiomorpholinyl, triazolyl or tropanyl. The heteroaryl groupsof the invention are substituted with 0, 1, 2, 3, 4 or 5 substituentsindependently selected from the group consisting of alkyl, alkenyl,alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkyenyloxy,alkynyloxy, carbocyclyloxy, heterocyclyloxy, haloalkoxy, fluoroalkyloxy,sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkyenylthio,alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl,fluoroalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl,haloalkoxysulfonyl, fluoroalkoxysulfonyl, alkenyloxysulfonyl,alkynyloxysulfony, aminosulfonyl, sulfinic acid, alkylsulfinyl,haloalkylsulfinyl, fluoroalkylsulfinyl, alkenylsulfinyl,alkynylsulfinyl, alkoxysulfinyl, haloalkoxysulfinyl,fluoroalkoxysulfinyl, alkenyloxysulfinyl, alkynyloxysulfiny,aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl,fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxyl,alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl,alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy,alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy,fluoroalkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy,haloalkoxysulfonyloxy, fluoroalkoxysulfonyloxy, alkenyloxysulfonyloxy,alkynyloxysulfonyloxy, alkylsulfinyloxy, haloalkylsulfinyloxy,fluoroalkylsulfinyloxy, alkenylsulfinyloxy, alkynylsulfinyloxy,alkoxysulfinyloxy, haloalkoxysulfinyloxy, fluoroalkoxysulfinyloxy,alkenyloxysulfinyloxy, alkynyloxysulfinyloxy, aminosulfinyloxy, amino,amido, aminosulfonyl, aminosulfinyl, cyano, nitro, azido, phosphinyl,phosphoryl, silyl, silyloxy, and any of said subsituents bound to theheteroaryl group through an alkylene moiety (e.g., methylene).

The term “heteroarylene,” is art-recognized, and as used herein pertainsto a diradical obtained by removing two hydrogen atoms of a heteroarylring, as defined above.

The term “heteroarylalkyl” or “heteroaralkyl” as used herein means aheteroaryl, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofheteroarylalkyl include, but are not limited to, pyridin-3-ylmethyl and2-(thien-2-yl)ethyl.

The term “fused bicyclyl” as used herein means the radical of a bicyclicring system wherein the two rings are ortho-fused, and each ring,contains a total of four, five, six or seven atoms (i.e., carbons andheteroatoms) including the two fusion atoms, and each ring can becompletely saturated, can contain one or more units of unsaturation, orcan be completely unsaturated (e.g., in some case, aromatic). For theavoidance of doubt, the degree of unsaturation in the fused bicyclyldoes not result in an aryl or heteroaryl moiety.

The term “halo” or “halogen” means —Cl, —Br, —I or —F.

The term “haloalkyl” means an alkyl group, as defined herein, wherein atleast one hydrogen is replaced with a halogen, as defined herein.Representative examples of haloalkyl include, but are not limited to,chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and2-chloro-3-fluoropentyl.

The term “fluoroalkyl” means an alkyl group, as defined herein, whereinsome or all of the hydrogens are replaced with fluorines.

The term “haloalkylene,” as used herein pertains to diradical obtainedby removing two hydrogen atoms of an haloalkyl group, as defined above.

The term “hydroxy” as used herein means an —OH group.

The term “alkoxy” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy. The terms “alkyenyloxy”, “alkynyloxy”, “carbocyclyloxy”, and“heterocyclyloxy” are likewise defined.

The term “haloalkoxy” as used herein means an alkoxy group, as definedherein, wherein at least one hydrogen is replaced with a halogen, asdefined herein. Representative examples of haloalkoxy include, but arenot limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, andpentafluoroethoxy. The term “fluoroalkyloxy” is likewise defined.

The term “aryloxy” as used herein means an aryl group, as definedherein, appended to the parent molecular moiety through an oxygen. Theterm “heteroaryloxy” as used herein means a heteroaryl group, as definedherein, appended to the parent molecular moiety through an oxygen. Theterms “heteroaryloxy” is likewise defined.

The term “arylalkoxy” or “arylalkyloxy” as used herein means anarylalkyl group, as defined herein, appended to the parent molecularmoiety through an oxygen. The term “heteroarylalkoxy” is likewisedefined. Representative examples of aryloxy and heteroarylalkoxyinclude, but are not limited to, 2-chlorophenylmethoxy,3-trifluoromethyl-phenylethoxy, and 2,3-dimethylpyridinylmethoxy.

The term “sulfhydryl” or “thio” as used herein means a —SH group.

The term “alkylthio” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfur.Representative examples of alkylthio include, but are not limited,methylthio, ethylthio, tert-butylthio, and hexylthio. The terms“haloalkylthio”, “fluoroalkylthio”, “alkyenylthio”, “alkynylthio”,“carbocyclylthio”, and “heterocyclylthio” are likewise defined.

The term “arylthio” as used herein means an aryl group, as definedherein, appended to the parent molecular moiety through an sulfur. Theterm “heteroarylthio” is likewise defined.

The term “arylalkylthio” or “aralkylthio” as used herein means anarylalkyl group, as defined herein, appended to the parent molecularmoiety through a sulfur. The term “heteroarylalkylthio” is likewisedefined.

The term “sulfonyl” as used herein refers to —S(═O)₂— group.

The term “sulfonic acid” as used herein refers to —S(═O)₂OH.

The term “alkylsulfonyl” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfonylgroup, as defined herein. Representative examples of alkylsulfonylinclude, but are not limited to, methylsulfonyl and ethylsulfonyl. Theterms “haloalkylsulfonyl”, “fluororalkylsulfonyl”, “alkenylsulfonyl”,“alkynylsulfonyl”, “carbocyclylsulfonyl”, “heterocyclylsulfonyl”,“arylsulfonyl”, “aralkylsulfonyl”, “heteroarylsulfonyl” and“heteroaralkylsulfonyl” are likewise defined.

The term “alkoxysulfonyl” as used herein means an alkoxy group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkoxysulfonyl include, but are not limited to, methoxysulfonyl,ethoxysulfonyl and propoxysulfonyl. The terms “haloalkoxysulfonyl”,“fluoroalkoxysulfonyl”, “alkenyloxysulfonyl”, “alkynyloxysulfonyl”,“carbocyclyloxysulfonyl”, “heterocyclyloxysulfonyl”, “aryloxysulfonyl”,“aralkyloxysulfonyl”, “heteroaryloxysulfonyl” and“heteroaralkyloxysulfonyl” are likewise defined.

The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized andrefer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl,and nonafluorobutanesulfonyl groups, respectively. The terms triflate,tosylate, mesylate, and nonaflate are art-recognized and refer totrifluoromethanesulfonate ester, p-toluenesulfonate ester,methanesulfonate ester, and nonafluorobutanesulfonate ester functionalgroups and molecules that contain said groups, respectively.

The term “aminosulfonyl” as used herein means an amino group, as definedherein, appended to the parent molecular moiety through a sulfonylgroup.

The term “sulfinyl” as used herein refers to —S(═O)— group. Sulfinylgroups are as defined above for sulfonyl groups. The term “sulfinicacid” as used herein refers to —S(═O)OH.

The term “oxy” refers to a —O— group.

The term “carbonyl” as used herein means a —C(═O)— group.

The term “thiocarbonyl” as used herein means a —C(═S)— group.

The term “formyl” as used herein means a —C(═O)H group.

The term “acyl” as used herein refers to any group or radical of theform —C(═O)R, where R is an organic group. An example of the acyl groupis the acetyl group (—C(═O)CH₃).

The term “alkylcarbonyl” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through a carbonylgroup, as defined herein. Representative examples of alkylcarbonylinclude, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl. The terms“haloalkylcarbonyl”, “fluoroalkylcarbonyl”, “alkenylcarbonyl”,“alkynylcarbonyl”, “carbocyclylcarbonyl”, “heterocyclylcarbonyl”,“arylcarbonyl”, “aralkylcarbonyl”, “heteroarylcarbonyl”, and“heteroaralkylcarbonyl” are likewise defined.

The term “carboxyl” as used herein means a —CO₂H group.

An “isostere of a carboxyl group” as used herein refers to a group whichis isosteric to a carboxyl group. Examples of isosters of a carboxylgroup include tetrazolyl, oxazolidinonyl, 3-isoxazolyl,hydroxyisoxazolyl, sulfonic acid, sulfinic acid, acylsulphonamide,phosphonic acid, phosphinic acid, hydantoin, pyrrolidionyl, boronicacid, hydroxamic acid, acylcyanamide and oxadiazolonyl.

The term “alkoxycarbonyl” as used herein means an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl. The terms “haloalkoxycarbonyl”,“fluoroalkoxycarbonyl”, “alkenyloxycarbonyl”, “alkynyloxycarbonyl”,“carbocyclyloxycarbonyl”, “heterocyclyloxycarbonyl”, “aryloxycarbonyl”,“aralkyloxycarbonyl”, “heteroaryloxycarbonyl”, and“heteroaralkyloxycarbonyl” are likewise defined.

The term “alkylcarbonyloxy” as used herein means an alkylcarbonyl group,as defined herein, appended to the parent molecular moiety through anoxygen atom. Representative examples of alkylcarbonyloxy include, butare not limited to, acetyloxy, ethylcarbonyloxy, andtert-butylcarbonyloxy. The terms “haloalkylcarbonyloxy”,“fluoroalkylcarbonyloxy”, “alkenylcarbonyloxy”, “alkynylcarbonyloxy”,“carbocyclylcarbonyloxy”, “heterocyclylcarbonyloxy”, “arylcarbonyloxy”,“aralkylcarbonyloxy”, “heteroarylcarbonyloxy”, and“heteroaralkylcarbonyloxy” are likewise defined.

The term “alkylsulfonyloxy” as used herein means an alkylsulfonyl group,as defined herein, appended to the parent molecular moiety through anoxygen atom. The terms “haloalkylsulfonyloxy”, “fluoroalkylsulfonyloxy”,“alkenylsulfonyloxy”, “alkynylsulfonyloxy”, “carbocyclylsulfonyloxy”,“heterocyclylsulfonyloxy”, “arylsulfonyloxy”, “aralkylsulfonyloxy”,“heteroarylsulfonyloxy”, “heteroaralkylsulfonyloxy”,“haloalkoxysulfonyloxy”, “fluoroalkoxysulfonyloxy”,“alkenyloxysulfonyloxy”, “alkynyloxysulfonyloxy”,“carbocyclyloxysulfonyloxy”, “heterocyclyloxysulfonyloxy”,“aryloxysulfonyloxy”, “aralkyloxysulfonyloxy”,“heteroaryloxysulfonyloxy” and “heteroaralkyloxysulfonyloxy” arelikewise defined.

The term “amino” or “amine” as used herein refers to —NH₂ andsubstituted derivatives thereof wherein one or both of the hydrogens areindependently replaced with substituents selected from the groupconsisting of alkyl, haloalkyl, fluoroalkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl,alkylcarbonyl, haloalkylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl,alkynylcarbonyl, carbocyclylcarbonyl, heterocyclylcarbonyl,arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyland the sulfonyl and sulfinyl groups defined above; or when bothhydrogens together are replaced with an alkylene group (to form a ringwhich contains the nitrogen). Representative examples include, but arenot limited to methylamino, acetylamino, and dimethylamino.

The term “amido” as used herein means an amino group, as defined herein,appended to the parent molecular moiety through a carbonyl.

The term “cyano” as used herein means a —C≡N group.

The term “nitro” as used herein means a —NO₂ group.

The term “azido” as used herein means a —N₃ group.

The term “phosphinyl” or “phosphino” as used herein includes —PH₃ andsubstituted derivatives thereof wherein one, two or three of thehydrogens are independently replaced with substituents selected from thegroup consisting of alkyl, haloalkyl, fluoroalkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl,alkoxy, haloalkoxy, fluoroalkyloxy, alkenyloxy, alkynyloxy,carbocyclyloxy, heterocyclyloxy, aryloxy, aralkyloxy, heteroaryloxy,heteroaralkyloxy, and amino.

The term “phosphoryl” as used herein refers to —P(═O)OH₂ and substitutedderivatives thereof wherein one or both of the hydroxyls areindependently replaced with substituents selected from the groupconsisting of alkyl, haloalkyl, fluoroalkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl,alkoxy, haloalkoxy, fluoroalkyloxy, alkenyloxy, alkynyloxy,carbocyclyloxy, heterocyclyloxy, aryloxy, aralkyloxy, heteroaryloxy,heteroaralkyloxy, and amino.

The term “silyl” as used herein includes H₃Si— and substitutedderivatives thereof wherein one, two or three of the hydrogens areindependently replaced with substitutents selected from alkyl,haloalkyl, fluoroalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aryl, aralkyl, heteroaryl, and heteroaralkyl. Representative examplesinclude trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS),tert-butyldimethylsilyl (TBS/TBDMS), triisopropylsilyl (TIPS), and[2-(trimethylsilyl)ethoxy]methyl (SEM).

The term “silyloxy” as used herein means a silyl group, as definedherein, is appended to the parent molecule through an oxygen atom.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl,ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl,p-toluenesulfonyl and methanesulfonyl, respectively. A morecomprehensive list of the abbreviations utilized by organic chemists ofordinary skill in the art appears in the first issue of each volume ofthe Journal of Organic Chemistry; this list is typically presented in atable entitled Standard List of Abbreviations.

The term “treating” as used herein, encompasses the administrationand/or application of one or more compounds described herein, to asubject, for the purpose of providing prevention of or management of,and/or remedy for a condition. “Treatment” for the purposes of thisdisclosure, may, but does not have to, provide a cure; rather,“treatment” may be in the form of management of the condition. When thecompounds described herein are used to treat unwanted proliferatingcells, including cancers, “treatment” includes partial or totaldestruction of the undesirable proliferating cells with minimaldestructive effects on normal cells. A desired mechanism of treatment ofunwanted rapidly proliferating cells, including cancer cells, at thecellular level is apoptosis.

The term “to treat” as used herein thus embraces not only to cure, butalso to slow the progression of and/or reduce the severity of a disease,disorder, or condition. In one embodiment, “treat” can encompass“prevent”.

The term “preventing” as used herein includes either preventing orslowing the onset of a clinically evident disease progression altogetheror preventing or slowing the onset of a preclinically evident stage of adisease in individuals at risk. This includes prophylactic treatment ofthose at risk of developing a disease.

The term “subject” for purposes of treatment includes any human oranimal subject who has been diagnosed with, has symptoms of, or is atrisk of developing a disorder. For methods of prevention the subject isany human or animal subject.

The term “optionally deuterated” as used herein refers to any radical,as described above, wherein one or more hydrogens has been replaced witha deuterium. Examples of deuterated alkyl include —CD₂H and —CD₃.

The term “polyol” as used herein refers to small molecules and polymerswhich have more than one hydroxyl.

As used herein, a “carbohydrate” (or, equivalently, a “sugar”) is asaccharide (including monosaccharides, oligosaccharides andpolysaccharides) and/or a molecule (including oligomers or polymers)derived from one or more monosaccharides, e.g., by reduction of carbonylgroups, by oxidation of one or more terminal groups to carboxylic acids,by replacement of one or more hydroxy group(s) by a hydrogen atom, anamino group, a thiol group or similar heteroatomic groups, etc. The term“carbohydrate” also includes derivatives of these compounds. In somecases, the carbohydrate may be a pentose (i.e., having 5 carbons) or ahexose (i.e., having 6 carbons); and in certain instances, thecarbohydrate may be an oligosaccharide comprising pentose and/or hexoseunits, e.g., including those described above.

“Carbohydrate” and “sugar” as used herein also includes sugar-mimeticsand sugar-like moieties. Sugar-mimetics are well known to one ofordinary skill in the art and include those described in detail in“Essentials of Glycobiology” Edited by Varki, A., et al, Cold SpringHarbor Laboratory Press. Cold Spring Harbor, N.Y. 2002. For example,sugar-mimetic groups contemplated by the present invention includecyclitols, such as a cycloalkane containing one hydroxyl group on eachof three or more ring atoms, as defined by IUPAC convention. In otherembodiments, such cyclitol moieties include inositols such asscyllo-inositol. Suitable sugar-like moieties include acyclic sugargroups. Such groups include linear alkylols and erythritols, to name buta few. It will be appreciated that sugar groups can exist in eithercyclic or acyclic form. Accordingly, acyclic forms of a sugar group arecontemplated by the present invention as a suitable sugar-like moieties.

The term “polythiol” as used herein refers to small molecules andpolymers which have more than one thiol.

Compounds

Niacin, also known as nicotinic acid, has the structure

One aspect of the invention relates to a compound represented bystructure I, or a pharmaceutically acceptable salt thereof:

wherein

-   -   R is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl,        heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl,        heteroaralkyl, fused bicyclyl, carboxyalkyl, or arylalkenylaryl;    -   R⁴ is selected independently for each occurrence from the group        consisting of deuterium, alkyl, alkenyl, alkynyl, aryl,        heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano,        sulfonic acid, alkylsulfoxyl, arylsulfoxyl, heteroarylsulfoxyl,        aralkylsulfoxyl, heteroaralkylsulfoxyl, alkenylsulfoxyl,        alkynylsulfoxyl, alkylsulfonyl, arylsulfonyl,        heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl,        alkenylsulfonyl, alkynylsulfonyl, hydroxyl, alkoxyl, aryloxyl,        heteroaryloxyl, aralkyloxy, heteroaralkyloxy, alkenyloxy,        alkynyloxy, thiol, alkylthio, arylthio, aralkylthio,        heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl,        formyloxy, acyloxy, formylthio, acylthio, amine, alkylamine,        arylamine, heteroarylamine, aralkylamine, heteroaralkylamine,        alkenylamine, alkynylamine, formylamine, acylamine, carboxyl,        alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,        aralkyloxycarbonyl, heteroaralkyloxycarbonyl, amido,        alkylaminecarbonyl, arylaminecarbonyl, heteroarylaminecarbonyl,        aralkylaminecarbonyl, and heteroaralkylaminecarbonyl;    -   R⁵ is hydrogen or lower alkyl;    -   n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and    -   m is 1, 2, 3, or 4.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein n is 0.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein n is 1.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein n is 2.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein n is 3.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein n is 1, 2, or 3; and R⁴ is substitutedindependently selected from the group consisting of lower alkyl,halogen, nitro, cyano, sulfonic acid, hydroxyl, alkoxyl, thiol,alkylthio, formyl, acyl, formyloxy, acyloxy, formylthio, acylthio,amine, alkylamine, formylamine, acylamine and carboxyl.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein n is 1; and R⁴ is selected from thegroup consisting of lower alkyl, halogen, nitro, cyano, sulfonic acid,hydroxyl, alkoxyl, thiol, alkylthio, formyl, acyl, formyloxy, acyloxy,formylthio, acylthio, amine, alkylamine, formylamine, acylamine andcarboxyl.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein m is 1.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein m is 2.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein m is 3.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein m is 4.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein R is hydrogen.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein R is lower alkyl.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein R is

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein R represents an aliphatic group whichis hydrolyzed to carboxyl under physiological conditions.

Another aspect of the invention relates to a compound, or apharmaceutically acceptable salt thereof, selected from the groupconsisting of

Another aspect of the invention relates to

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention relates to a compound represented bystructure II, or a pharmaceutically acceptable salt thereof,

R¹)_(p)  II

-   -   wherein, independently for each occurrence,    -   W is a polyol or polythiol;    -   p is 2-500 inclusive;

R¹ is

and is either appended to the polyol through an oxygen atom of thepolyol or is appended to the polythiol through a sulfur atom of thepolythiol;

-   -   R⁴ is selected independently for each occurrence from the group        consisting of deuterium, alkyl, alkenyl, alkynyl, aryl,        heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano,        sulfonic acid, alkylsulfoxyl, arylsulfoxyl, heteroarylsulfoxyl,        aralkylsulfoxyl, heteroaralkylsulfoxyl, alkenylsulfoxyl,        alkynylsulfoxyl, alkylsulfonyl, arylsulfonyl,        heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl,        alkenylsulfonyl, alkynylsulfonyl, hydroxyl, alkoxyl, aryloxyl,        heteroaryloxyl, aralkyloxy, heteroaralkyloxy, alkenyloxy,        alkynyloxy, thiol, alkylthio, arylthio, aralkylthio,        heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl,        formyloxy, acyloxy, formylthio, acylthio, amine, alkylamine,        arylamine, heteroarylamine, aralkylamine, heteroaralkylamine,        alkenylamine, alkynylamine, formylamine, acylamine, carboxyl,        alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,        aralkyloxycarbonyl, heteroaralkyloxycarbonyl, amido,        alkylaminecarbonyl, arylaminecarbonyl, heteroarylaminecarbonyl,        aralkylaminecarbonyl, and heteroaralkylaminecarbonyl;    -   R⁵ is selected independently for each occurrence from the group        consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,        heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano,        sulfonic acid, alkylsulfoxyl, arylsulfoxyl, heteroarylsulfoxyl,        aralkylsulfoxyl, heteroaralkylsulfoxyl, alkenylsulfoxyl,        alkynylsulfoxyl, alkylsulfonyl, arylsulfonyl,        heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl,        alkenylsulfonyl, alkynylsulfonyl, hydroxyl, alkoxyl, aryloxyl,        heteroaryloxyl, aralkyloxy, heteroaralkyloxy, alkenyloxy,        alkynyloxy, thiol, alkylthio, arylthio, aralkylthio,        heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl,        formyloxy, acyloxy, formylthio, acylthio, amine, alkylamine,        arylamine, heteroarylamine, aralkylamine, heteroaralkylamine,        alkenylamine, alkynylamine, formylamine, acylamine, carboxyl,        alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,        aralkyloxycarbonyl, heteroaralkyloxycarbonyl, amido,        alkylaminecarbonyl, arylaminecarbonyl, heteroarylaminecarbonyl,        aralkylaminecarbonyl, and heteroaralkylaminecarbonyl;    -   n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and    -   m is 1, 2, 3, or 4.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein W is a polythiol.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein W is a polyol.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein said polyol is a carbohydrate.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein said polyol is maltitol, sorbitol,xylitol and isomalt.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein said polyol is sorbitol.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein said polyol is inositol.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein said polyol iscis-1,2,3,5-trans-4,6-cyclohexanehexyl.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein p is 2, 3, 4, 5, or 6.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein p is 2-100 inclusive. In certainembodiments, the invention relates to any one of the aforementionedcompounds, wherein p is 2-50 inclusive. In certain embodiments, theinvention relates to any one of the aforementioned compounds, wherein pis 2-10 inclusive.

In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein p is 2. In certain embodiments, theinvention relates to any one of the aforementioned compounds, wherein pis 3. In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein p is 4. In certain embodiments, theinvention relates to any one of the aforementioned compounds, wherein pis 5. In certain embodiments, the invention relates to any one of theaforementioned compounds, wherein p is 6.

Another aspect of the invention relates to a compound, or apharmaceutically acceptable salt thereof, selected from the groupconsisting of

It has been discovered that at least certain of the compounds of theinvention have desirable physiological attributes of niacin, withreduced undesirable physiological side effects of niacin. For example,compounds of the invention have the ability to modulate at least onelipid in a desirable fashion, without restrictive side effects, orwithout the degree of restrictive side effects, characteristic ofniacin.

Additionally, it has been discovered that at least certain of thecompounds of the invention do not appear to engage the high-affinityniacin receptor GPR109A in a manner similar to niacin. GPR109A, alsoreferred to as PUMA-G and HM74A, is a member of the nicotinic acidreceptor family of G protein-coupled redeptors (GPCRs). Wise A et al.(2003) J Biol Chem 278:99-74; Soga T et al. (2003) Biochem Biophys ResComm 303:364-9. In GPR109A knockout mice, the effects of niacin on bothlipids and flushing are eliminated. The flushing effect, but not thelipid modifying effects, of niacin has been ascribed to GPR109Aactivation of ERK 1/2 MAP kinase, mediated by arrestin beta 1 (beta(β)-arrestin). In arrestin beta 1 knockout mice, niacin's effect onflushing has been reported to be greatly reduced while the lipidmodifying effects are maintained. Walters R W et al. (2009) J ClinInvest 119:1312-21. Significantly, at least certain of the compounds ofthe invention have greatly reduced ability to induce recruitment ofβ-arrestin to the membrane of cells expressing GPR109A, have greatlyreduced flushing effect compared to niacin, yet maintain clinicallysignificant desirable lipid-modifying effects.

Many of the compounds of the invention may be provided as salts withpharmaceutically compatible counterions (i.e., pharmaceuticallyacceptable salts). A “pharmaceutically acceptable salt” means anynon-toxic salt that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound or a prodrug of acompound of this invention. A “pharmaceutically acceptable counterion”is an ionic portion of a salt that is not toxic when released from thesalt upon administration to a recipient. Pharmaceutically compatiblesalts may be formed with many acids, including but not limited tohydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.Salts tend to be more soluble in aqueous or other protonic solvents thanare the corresponding free base forms.

Acids commonly employed to form pharmaceutically acceptable saltsinclude inorganic acids such as hydrogen bisulfide, hydrochloric,hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well asorganic acids such as para-toluenesulfonic, salicylic, tartaric,bitartaric, ascorbic, maleic, besylic, fumaric, gluconic, glucuronic,formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic,lactic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric,benzoic and acetic acid, and related inorganic and organic acids. Suchpharmaceutically acceptable salts thus include sulfate, pyrosulfate,bisulfate, sulfite, bisulfate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephathalate, sulfonate, xylenesulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycolate, maleate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the likesalts. Exemplary pharmaceutically acceptable acid addition salts includethose formed with mineral acids such as hydrochloric acid andhydrobromic acid, and especially those formed with organic acids such asmaleic acid.

Suitable bases for forming pharmaceutically acceptable salts with acidicfunctional groups include, but are not limited to, hydroxides of alkalimetals such as sodium, potassium, and lithium; hydroxides of alkalineearth metal such as calcium and magnesium; hydroxides of other metals,such as aluminum and zinc; ammonia, and organic amines, such asunsubstituted or hydroxy-substituted mono-, di-, or trialkylamines;dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine;diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkylamines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike.

Certain compounds of the invention and their salts may exist in morethan one crystal form and the present invention includes each crystalform and mixtures thereof.

Certain compounds of the invention and their salts may also exist in theform of solvates, for example hydrates, and the present inventionincludes each solvate and mixtures thereof.

Certain compounds of the invention may contain one or more chiralcenters, and exist in different optically active forms. When compoundsof the invention contain one chiral center, the compounds exist in twoenantiomeric forms and the present invention includes both enantiomersand mixtures of enantiomers, such as racemic mixtures. The enantiomersmay be resolved by methods known to those skilled in the art, forexample by formation of diastereoisomeric salts which may be separated,for example, by crystallization; formation of diastereoisomericderivatives or complexes which may be separated, for example, bycrystallization, gas-liquid or liquid chromatography; selective reactionof one enantiomer with an enantiomer-specific reagent, for exampleenzymatic esterification; or gas-liquid or liquid chromatography in achiral environment, for example on a chiral support for example silicawith a bound chiral ligand or in the presence of a chiral solvent. Itwill be appreciated that where the desired enantiomer is converted intoanother chemical entity by one of the separation procedures describedabove, a further step may be used to liberate the desired enantiomericform. Alternatively, specific enantiomers may be synthesized byasymmetric synthesis using optically active reagents, substrates,catalysts or solvents, or by converting one enantiomer into the other byasymmetric transformation.

When a compound of the invention contains more than one chiral center,it may exist in diastereoisomeric forms. The diastereoisomeric compoundsmay be separated by methods known to those skilled in the art, forexample chromatography or crystallization and the individual enantiomersmay be separated as described above. The present invention includes eachdiastereoisomer of compounds of the invention and mixtures thereof.

Certain compounds of the invention may exist in different tautomericforms or as different geometric isomers, and the present inventionincludes each tautomer and/or geometric isomer of compounds of theinvention and mixtures thereof.

Certain compounds of the invention may exist in different stableconformational forms which may be separable. Torsional asymmetry due torestricted rotation about an asymmetric single bond, for example becauseof steric hindrance or ring strain, may permit separation of differentconformers. The present invention includes each conformational isomer ofcompounds of the invention and mixtures thereof.

Certain compounds of the invention may exist in zwitterionic form andthe present invention includes each zwitterionic form of compounds ofthe invention and mixtures thereof.

The present invention also includes prodrugs. As used herein the term“prodrug” refers to an agent which is converted into the parent drug invivo by some physiological chemical process (e.g., a prodrug on beingbrought to the physiological pH is converted to the desired drug form).Pro-drugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent drug is not. Theprodrug may also have improved solubility in pharmacologicalcompositions over the parent drug. An example, without limitation, of aprodrug would be a compound of the present invention wherein it isadministered as an ester (the “prodrug”) to facilitate transmittalacross a cell membrane where water solubility is not beneficial, butthen it is metabolically hydrolyzed to the carboxylic acid once insidethe cell where water solubility is beneficial. Pro-drugs have manyuseful properties. For example, a prodrug may be more water soluble thanthe ultimate drug, thereby facilitating intravenous administration ofthe drug. A prodrug may also have a higher level of oral bioavailabilitythan the ultimate drug. After administration, the prodrug isenzymatically or chemically cleaved to deliver the ultimate drug in theblood or tissue.

Exemplary prodrugs upon cleavage release the corresponding free acid,and such hydrolyzable ester-forming residues of the compounds of thisinvention include but are not limited to carboxylic acid substituents(e.g., —C(O)₂H or a moiety that contains a carboxylic acid) wherein thefree hydrogen is replaced by (C₁-C₄)alkyl, (C₂-C₁₂)alkanoyloxymethyl,(C₄-C₉)1-(alkanoyloxy)ethyl, 1-methyl-1-(alkanoyloxy)-ethyl having from5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbonatoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)-alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

Other exemplary prodrugs release an alcohol or amine of a compound ofthe invention wherein the free hydrogen of a hydroxyl or aminesubstituent is replaced by (C₁-C₆)alkanoyloxymethyl,1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl,(C₁-C₆)alkoxycarbonyl-oxymethyl, N—(C₁-C₆)alkoxycarbonylamino-methyl,succinoyl, (C₁-C₆)alkanoyl, α-amino(C₁-C₄)alkanoyl, arylactyl andα-aminoacyl, or α-aminoacyl-α-aminoacyl wherein said α-aminoacylmoieties are independently any of the naturally occurring L-amino acidsfound in proteins, —P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (theradical resulting from detachment of the hydroxyl of the hemiacetal of acarbohydrate).

The phrase “protecting group” as used herein means temporarysubstituents which protect a potentially reactive functional group fromundesired chemical transformations. Examples of such protecting groupsinclude esters of carboxylic acids, silyl ethers of alcohols, andacetals and ketals of aldehydes and ketones, respectively. The field ofprotecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G.M. Protective Groups in Organic Synthesis, 2^(nd) ed.; Wiley: New York,1991). Protected forms of the inventive compounds are included withinthe scope of this invention.

The term “chemically protected form,” as used herein, pertains to acompound in which one or more reactive functional groups are protectedfrom undesirable chemical reactions, that is, are in the form of aprotected or protecting group (also known as a masked or masking group).It may be convenient or desirable to prepare, purify, and/or handle theactive compound in a chemically protected form.

By protecting a reactive functional group, reactions involving otherunprotected reactive functional groups can be performed, withoutaffecting the protected group; the protecting group may be removed,usually in a subsequent step, without substantially affecting theremainder of the molecule. See, for example, Protective Groups inOrganic Synthesis (T. Green and P. Wuts, Wiley, 1991), and ProtectiveGroups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; JohnWiley and Sons, 1999).

For example, a hydroxy group may be protected as an ether (—OR) or anester (—OC(═O)R), for example, as: a t-butyl ether; a benzyl,benzhydryl(diphenylmethyl), or trityl(triphenylmethyl)ether; atrimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester(—OC(═O)CH₃, —OAc).

For example, an aldehyde or ketone group may be protected as an acetalor ketal, respectively, in which the carbonyl group (C(═O)) is convertedto a diether (C(OR)₂), by reaction with, for example, a primary alcohol.The aldehyde or ketone group is readily regenerated by hydrolysis usinga large excess of water in the presence of acid.

For example, an amine group may be protected, for example, as an amide(—NRC(═O)R) or a urethane (—NRC(═O)OR), for example, as: a methyl amide(—NHC(═O)CH₃); a benzyloxy amide (—NHC(═O)OCH₂C₆H₅NHCbz); as a t-butoxyamide (—NHC═(═O)OC(CH₃)₃, —NHBoc); a 2-biphenyl-2-propoxy amide(—NHC(═O)OC(CH₃)₂C₆H₄C₆H₅NHBoc), as a 9-fluorenylmethoxy amide(—NHFmoc), as a 6-nitroveratryloxy amide (—NHNvoc), as a2-trimethylsilylethyloxy amide (—NHTeoc), as a 2,2,2-trichloroethyloxyamide (—NHTroc), as an allyloxy amide (—NHAlloc), as a2-(phenylsulfonyl)ethyloxy amide (—NHPsec); or, in suitable cases (e.g.,cyclic amines), as a nitroxide radical.

For example, a carboxylic acid group may be protected as an ester or anamide, for example, as: a benzyl ester; a t-butyl ester; a methyl ester;or a methyl amide.

For example, a thiol group may be protected as a thioether (—SR), forexample, as: a benzyl thioether; or an acetamidomethyl ether(—SCH₂NHC(═O)CH₃).

Pharmaceutical Compositions

The invention provides pharmaceutical compositions comprising one ormore of the above-referenced compounds. In one aspect, the presentinvention provides pharmaceutically acceptable compositions whichcomprise a therapeutically effective amount of one or more of thecompounds described above, formulated together with one or morepharmaceutically acceptable carriers (additives) and/or diluents.

Alternatively or in addition, the invention provides pharmaceuticalcompositions characterized by having at least one desired therapeuticeffect of niacin and a reduction or absence of at least one undesirableside effect of niacin.

In one embodiment, the pharmaceutical composition is formulated for oraladministration; when administered orally to a human reduces a serum orplasma level of at least one lipid selected from the group consisting oftotal cholesterol, low-density lipoprotein (LDL) cholesterol,triglycerides, and lipoprotein (a); and oral administration of thecomposition is characterized by reduced flushing and reducedhepatocellular damage, as compared to administration of an equimolaroral dose of niacin.

The pharmaceutical composition, when administered orally to a human,reduces a serum or plasma level of at least one lipid selected from thegroup consisting of total cholesterol, low-density lipoprotein (LDL)cholesterol, triglycerides, and lipoprotein (a). The composition is saidto reduce a serum or plasma level of at least one lipid when such serumor plasma level is reduced by a measurable amount as compared to apre-treatment, baseline, or control level. In one embodiment, thecomposition is said to reduce a serum or plasma level of at least onelipid when such serum or plasma level is reduced by at least 5 percentof the pre-treatment, baseline, or control level; that is, the serum orplasma level is reduced to no more than 95 percent of the pre-treatment,baseline, or control level. In one embodiment, the composition is saidto reduce a serum or plasma level of at least one lipid when such serumor plasma level is reduced by at least 10 percent of the pre-treatment,baseline or control level. In one embodiment, the composition is said toreduce a serum or plasma level of at least one lipid when such serum orplasma level is reduced by at least 15 percent of the pretreatment,baseline or control level. In one embodiment, the composition is said toreduce a serum or plasma level of at least one lipid when such serum orplasma level is reduced by at least 20 percent of the pretreatment,baseline or control level.

As used herein, “flushing” refers to objective cutaneous vasodilation,frequently accompanied by redness and/or a subjective experience of awarm feeling in the skin, the latter with or without itching. Flushingcan be measured objectively using objective measurements such as Dopplercapillary blood flow measurements. Alternatively or in addition,flushing can be measured using a so-called visual analog scale (VAS),which can be either observer-based or subject-based. The VAS typicallyinvolves scoring a sign or symptom on a scale ranging from zero (0) toten (10), where zero corresponds to complete absence of the sign orsymptom being scored, and ten corresponds to an unbearable or maximumamount or degree of the sign or symptom being scored.

As used herein, “hepatocellular damage” refers to toxic injury to liverparenchymal cells. Hepatocellular damage can be assessed using anysuitable method. In one embodiment, hepatocellular damage is assessed bymeasuring one or more serum liver enzymes. In one embodiment, one suchliver enzyme is aspartate aminotransferase (AST, also referred to asSGOT). In one embodiment, one such liver enzyme is alanineaminotransferase (ALT, also referred to as SGPT). Serum levels of ASTand ALT are commonly measured in clinical practice, and it is notnecessary to describe methods for their measurement here. Normal serumlevels both of AST and ALT are generally 0-35 U/L. In contrast to ALT,which is found primarily in the liver, AST is also found in othertissues, including heart, skeletal muscle, kidney, and brain, and isthus somewhat less specific as an indicator of liver dysfunction.Although elevated serum levels of AST or ALT may be observed in avariety of nonhepatic conditions, including myocardial infarction, theseconditions are usually readily distinguished clinically from liverdisease. In liver disease, elevations of serum AST and ALT reflecthepatic necrosis, a severe form of hepatocellular damage.

Oral administration of the composition is characterized by reducedflushing and reduced hepatocellular damage, as compared toadministration of an equimolar oral dose of niacin. In this context,flushing is said to be reduced when it is reduced by a measurable amountor degree as compared to a corresponding degree of flushing associatedwith administration of an equimolar oral dose of niacin. In oneembodiment, flushing is said to be reduced when the maximum degree oramount of flushing is reduced by a measurable degree or amount ascompared to the maximum degree or amount of flushing associated withadministration of an equimolar oral dose of niacin.

In one embodiment, flushing is said to be reduced when Doppler capillaryblood flow in relevant tissue is reduced by at least 2 percent ascompared to Doppler capillary blood flow in corresponding relevanttissue associated with administration of an equimolar oral dose ofniacin; i.e., the flow is reduced to no more than 98 percent of theDoppler capillary blood flow in corresponding relevant tissue associatedwith administration of an equimolar oral dose of niacin. In oneembodiment, flushing is said to be reduced when Doppler capillary bloodflow in relevant tissue is reduced by at least 5 percent as compared toDoppler capillary blood flow in corresponding relevant tissue associatedwith administration of an equimolar oral dose of niacin. In oneembodiment, flushing is said to be reduced when Doppler capillary bloodflow in relevant tissue is reduced by at least 10 percent as compared toDoppler capillary blood flow in corresponding relevant tissue associatedwith administration of an equimolar oral dose of niacin.

In one embodiment, flushing is said to be reduced when VAS score forrelevant tissue is reduced by at least one (1) (on a scale from 0 to 10)as compared to VAS score for corresponding relevant tissue associatedwith administration of an equimolar oral dose of niacin; i.e., the VASscore reduced to no more than one less than the VAS score forcorresponding relevant tissue associated with administration of anequimolar oral dose of niacin. For example, in one such an embodiment,flushing is said to be reduced when the maximum VAS score is 5 whereasthe maximum VAS score for corresponding relevant tissue associated withadministration of an equimolar oral dose of niacin is 6-10.

Of course, any of the foregoing comparisons can, advantageously, be madeon a population basis. For example, mean or median values of AST, ALT,or VAS score can be compared. Likewise, mean or median values of maximumAST, maximum ALT, or maximum VAS score can be compared.

Comparison is made to an equimolar oral dose of niacin. An equimolaroral dose of niacin refers to an equimolar oral dose of niacin in anyform, including, for example immediate-, timed-, sustained-, andextended-release formulations of niacin. In one embodiment, an equimolaroral dose is formulated in an analogous fashion, e.g., in tablet formwherein each individual tablet is comprised of the same or essentiallythe same molar amount of active agent. Thus, for example, comparison canbe made, in one embodiment, between oral doses given as single tablets,each tablet containing 8.2 mmol of active agent (e.g., 1 g of niacin).As an alternative example, comparison can be made, in anotherembodiment, between oral doses given as two single tablets, each tabletcontaining 4.1 mmol of active agent (e.g., 0.5 g of niacin).

Except as may be indicated otherwise herein, all pharmacokineticcomparisons to “niacin” are comparisons to so-called immediate-releaseformulation of niacin.

In certain embodiments, the invention relates to any one of theaforementioned compositions, wherein peak serum or plasma concentration(C_(max)) for the compound is 40 percent or less of C_(max) for theequimolar oral dose of niacin. In one embodiment, peak serum or plasmaconcentration (C_(max)) for the compound is 35 percent or less ofC_(max) for the equimolar oral dose of niacin. In one embodiment, peakserum or plasma concentration (C_(max)) for the compound is 30 percentor less of C_(max) for the equimolar oral dose of niacin. In oneembodiment, peak serum or plasma concentration (C_(max)) for thecompound is 25 percent or less of C_(max) for the equimolar oral dose ofniacin. In one embodiment, peak serum or plasma concentration (C_(max))for the compound is 20 percent or less of C_(max) for the equimolar oraldose of niacin. In one embodiment, peak serum or plasma concentration(C_(max)) for the compound is 15 percent or less of C_(max) for theequimolar oral dose of niacin. In one embodiment, peak serum or plasmaconcentration (C_(max)) for the compound is 10 percent or less ofC_(max) for the equimolar oral dose of niacin. In one embodiment, peakserum or plasma concentration (C_(max)) for the compound is 5 percent orless of C_(max) for the equimolar oral dose of niacin. In oneembodiment, peak serum or plasma concentration (C_(max)) for thecompound is 1 percent or less of C_(max) for the equimolar oral dose ofniacin. For each of the foregoing embodiments, it is to be understoodthat comparison is made with an immediate release formulation of niacin.Methods useful for measuring the concentration are disclosed in detailherein below.

In certain embodiments, the invention relates to any one of theaforementioned compositions, wherein peak serum or plasma concentration(C_(max)) for the compound is 1 to 40 percent of C_(max) for theequimolar oral dose of niacin. In one embodiment, peak serum or plasmaconcentration (C_(max)) for the compound is 1 to 35 percent of C_(max)for the equimolar oral dose of niacin. In one embodiment, peak serum orplasma concentration (C_(max)) for the compound is 1 to 30 percent ofC_(max) for the equimolar oral dose of niacin. In one embodiment, peakserum or plasma concentration (C_(max)) for the compound is 1 to 25percent of C_(max) for the equimolar oral dose of niacin. In oneembodiment, peak serum or plasma concentration (C_(max)) for thecompound is 1 to 20 percent of C_(max) for the equimolar oral dose ofniacin. In one embodiment, peak serum or plasma concentration (C_(max))for the compound is 1 to 15 percent of C_(max) for the equimolar oraldose of niacin. In one embodiment, peak serum or plasma concentration(C_(max)) for the compound is 1 to 10 percent of C_(max) for theequimolar oral dose of niacin. For each of the foregoing embodiments, itis to be understood that comparison is made with an immediate releaseformulation of niacin. Methods useful for measuring the concentrationare disclosed in detail hereinbelow.

In certain embodiments, the invention relates to any one of theaforementioned compositions, wherein the ratio of peak serum or plasmaconcentration (C_(max)) to area under the curve at 24 hours (AUC₀₋₂₄)(i.e., the ratio C_(max)/AUC₀₋₂₄) for the compound is 0.35 h⁻¹ or less.In one embodiment, the ratio of peak concentration to area under thecurve at 24 hours (C_(max)/AUC₀₋₂₄) for the compound is 0.30 h⁻¹ orless. In one embodiment, the ratio of peak concentration to area underthe curve at 24 hours (C_(max)/AUC₀₋₂₄) for the compound is 0.25 h⁻¹ orless. In one embodiment, the ratio of peak concentration to area underthe curve at 24 hours (C_(max)/AUC₀₋₂₄) for the compound is 0.20 h⁻¹ orless. In one embodiment, the ratio of peak concentration to area underthe curve at 24 hours (C_(max)/AUC₀₋₂₄) for the compound is 0.15 h⁻¹ orless. In one embodiment, the ratio of peak concentration to area underthe curve at 24 hours (C_(max)/AUC₀₋₂₄) for the compound is 0.10 h⁻¹ orless. In one embodiment, the ratio of peak concentration to area underthe curve at 24 hours (C_(max)/AUC₀₋₂₄) for the compound is 0.05 h⁻¹ orless. In one embodiment, the ratio of peak concentration to area underthe curve at 24 hours (C_(max)/AUC₀₋₂₄) for the compound is 0.01 h⁻¹ orless.

In certain embodiments, the invention relates to any one of theaforementioned compositions, wherein the ratio of peak serum or plasmaconcentration (C_(max)) to area under the curve at 24 hours (AUC₀₋₂₄)(i.e., the ratio C_(max)/AUC₀₋₂₄) for the compound is 0.10 h⁻¹ to 0.35h⁻¹. In one embodiment, the ratio of peak concentration to area underthe curve at 24 hours (C_(max)/AUC₀₋₂₄) for the compound is 0.10 h⁻¹ to0.30 h⁻¹. In one embodiment, the ratio of peak concentration to areaunder the curve at 24 hours (C_(max)/AUC₀₋₂₄) for the compound is 0.10h⁻¹ to 0.25 h⁻¹. In one embodiment, the ratio of peak concentration toarea under the curve at 24 hours (C_(max)/AUC₀₋₂₄) for the compound is0.10 h⁻¹ to 0.20 h⁻¹.

In certain embodiments, the invention relates to any one of theaforementioned compositions, wherein the time to peak serum or plasmaconcentration (t_(max)) for the compound is in the range of 30 minutesto 5 hours. In one embodiment, the time to peak concentration (t_(max))for the compound is in the range of 1 to 5 hours. In one embodiment, thetime to peak concentration (t_(max)) for the compound is in the range of1 to 4 hours. In one embodiment, the time to peak concentration(t_(max)) for the compound is in the range of 1 to 3 hours. In oneembodiment, the time to peak concentration (t_(max)) for the compound isin the range of 1 to 2 hours.

In certain embodiments, the invention relates to any one of theaforementioned compositions, wherein the compound has an EC₅₀ forβ-arrestin-mediated GPR109A function which is at least 10 times greaterthan the EC₅₀ of niacin for β-arrestin-mediated GPR109A function. EC₅₀refers to the concentration at which a particular effect achieves 50percent of its maximum. β-arrestin-mediated GPR109A function isdescribed elsewhere herein. In one embodiment, the compound has an EC₅₀for β-arrestin-mediated GPR109A function which is at least 20 timesgreater than the EC₅₀ of niacin for β-arrestin-mediated GPR109Afunction. In one embodiment, the compound has an EC₅₀ forβ-arrestin-mediated GPR109A function which is at least 30 times greaterthan the EC₅₀ of niacin for β-arrestin-mediated GPR109A function. In oneembodiment, the compound has an EC₅₀ for β-arrestin-mediated GPR109Afunction which is at least 40 times greater than the EC₅₀ of niacin forβ-arrestin-mediated GPR109A function. In one embodiment, the compoundhas an EC₅₀ for β-arrestin-mediated GPR109A function which is at least50 times greater than the EC₅₀ of niacin for β-arrestin-mediated GPR109Afunction. In one embodiment, the compound has an EC₅₀ forβ-arrestin-mediated GPR109A function which is at least 100 times greaterthan the EC₅₀ of niacin for 3-arrestin-mediated GPR109A function.

In certain embodiments, the invention relates to any one of theaforementioned compositions, wherein the composition, when administeredorally to a human, also increases a serum or plasma level ofhigh-density lipoprotein (HDL) cholesterol. The serum or plasma level ofHDL cholesterol increases by at least a measurable amount compared to apretreatment, baseline, or control level. For example, in oneembodiment, serum or plasma level of HDL cholesterol increases by atleast 5 percent compared to a pre-treatment, baseline, or control level.In one embodiment, serum or plasma level of HDL cholesterol increases byat least 10 percent compared to a pre-treatment, baseline, or controllevel. In one embodiment, serum or plasma level of HDL cholesterolincreases by at least 15 percent compared to a pretreatment, baseline,or control level. In one embodiment, serum or plasma level of HDLcholesterol increases by at least 20 percent compared to apre-treatment, baseline, or control level. In one embodiment, serum orplasma level of HDL cholesterol increases by at least 25 percentcompared to a pre-treatment, baseline, or control level.

In certain embodiments, the invention relates to any one of theaforementioned compositions, wherein the composition, when administeredorally to a human, induces substantially no increase in serum levels ofaspartate aminotransferase (AST), alanine aminotransferase (ALT), orboth. In one embodiment, “substantially no increase” in this contextmeans less than a 20 percent increase over a pre-treatment, baseline, orcontrol level. In one embodiment, “substantially no increase” means lessthan a 10 percent increase over a pre-treatment, baseline, or controllevel.

In certain embodiments, the invention relates to any one of theaforementioned compositions, wherein the composition, when administeredorally to a human, induces substantially no increase in serum levels ofuric acid, glucose, or both. Normal serum levels of uric acid are1.5-8.0 mg/dL. In one embodiment, “substantially no increase in serumlevel of uric acid” means less than a 10 percent increase over apre-treatment, baseline, or control level. Normal fasting plasma levelsof glucose are ca. 75-115 mg/dL. Normal random (2 h postprandial) plasmalevels of glucose are ca. <140 mg/dL. In one embodiment, “substantiallyno increase in serum level of glucose” means less than a 20 percentincrease over a pre-treatment, baseline, or control level. In oneembodiment, “substantially no increase in serum level of glucose” meansless than a 15 percent increase over a pretreatment, baseline, orcontrol level. In one embodiment, “substantially no increase in serumlevel of glucose” means less than a 10 percent increase over apre-treatment, baseline, or control level.

In another aspect, the agents of the invention can be administered assuch, or administered in mixtures with pharmaceutically acceptablecarriers and can also be administered in conjunction with other agents.Conjunctive therapy thus includes sequential, simultaneous and separate,or co-administration of one or more compound of the invention, whereinthe therapeutic effects of the first administered has not entirelydisappeared when the subsequent compound is administered. In otherwords, the terms “co-administration” and “co-administering,” as usedherein, refer to both concurrent administration (administration of twoor more therapeutic agents at the same time) and time variedadministration (administration of one or more therapeutic agents at atime different from that of the administration of an additionaltherapeutic agent or agents), as long as the therapeutic agents arepresent in the patient to some extent at the same time.

As described in detail below, the pharmaceutical compositions of thepresent invention may be specially formulated for administration insolid or liquid form, including those adapted for the following: (1)oral administration, for example, drenches (aqueous or non-aqueoussolutions or suspensions), tablets, e.g., those targeted for buccal,sublingual, and systemic absorption, capsules, boluses, powders,granules, pastes for application to the tongue; (2) parenteraladministration, for example, by intravenous, intramuscular,intraperitoneal, subcutaneous, or epidural injection or infusion as, forexample, a sterile solution or suspension, or sustained-releaseformulation; (3) topical application, for example, as a cream, ointment,or a controlled-release patch or spray applied to the skin; (4)intravaginally or intrarectally, for example, as a pessary, cream orfoam; (5) sublingually; (6) ocularly; (7) transdermally; (8) nasally;(9) pulmonary; or (10) intrathecally.

The phrase “therapeutically effective amount” as used herein means thatamount of a compound, material, or composition comprising a compound ofthe present invention which is effective for producing some desiredtherapeutic effect in at least a sub-population of cells in an animal ata reasonable benefit/risk ratio applicable to any medical treatment.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically-acceptable carrier” as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, manufacturing aid (e.g.,lubricant, talc magnesium, calcium or zinc stearate, or steric acid), orsolvent encapsulating material, involved in carrying or transporting thesubject compound from one organ, or portion of the body, to anotherorgan, or portion of the body. Each carrier must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not injurious to the patient. Some examples of materials which canserve as pharmaceutically-acceptable carriers include: (1) sugars, suchas lactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) pH buffered solutions; (21)polyesters, polycarbonates and/or polyanhydrides; and (22) othernon-toxic compatible substances employed in pharmaceutical formulations.

As set out above, certain embodiments of the present compounds maycontain a basic functional group, such as amino or alkylamino, and are,thus, capable of forming pharmaceutically-acceptable salts withpharmaceutically-acceptable acids. The term “pharmaceutically-acceptablesalts” in this respect, refers to the relatively non-toxic, inorganicand organic acid addition salts of compounds of the present invention.These salts can be prepared in situ in the administration vehicle or thedosage form manufacturing process, or by separately reacting a purifiedcompound of the invention in its free base form with a suitable organicor inorganic acid, and isolating the salt thus formed during subsequentpurification. Representative salts include the hydrobromide,hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate,valerate, oleate, palmitate, stearate, laurate, benzoate, lactate,phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate,napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonatesalts and the like. (See, for example, Berge et al. (1977)“Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19).

The pharmaceutically acceptable salts of the subject compounds includethe conventional nontoxic salts or quaternary ammonium salts of thecompounds, e.g., from non-toxic organic or inorganic acids. For example,such conventional nontoxic salts include those derived from inorganicacids such as hydrochloride, hydrobromic, sulfuric, sulfamic,phosphoric, nitric, and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicyclic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isothionic, and the like.

In other cases, the compounds of the present invention may contain oneor more acidic functional groups and, thus, are capable of formingpharmaceutically-acceptable salts with pharmaceutically-acceptablebases. The term “pharmaceutically-acceptable salts” in these instancesrefers to the relatively non-toxic, inorganic and organic base additionsalts of compounds of the present invention. These salts can likewise beprepared in situ in the administration vehicle or the dosage formmanufacturing process, or by separately reacting the purified compoundin its free acid form with a suitable base, such as the hydroxide,carbonate or bicarbonate of a pharmaceutically-acceptable metal cation,with ammonia, or with a pharmaceutically-acceptable organic primary,secondary or tertiary amine Representative alkali or alkaline earthsalts include the lithium, sodium, potassium, calcium, magnesium, andaluminum salts and the like. Representative organic amines useful forthe formation of base addition salts include ethylamine, diethylamine,ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.(See, for example, Berge et al., supra)

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated, the particular mode ofadministration. The amount of active ingredient which can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound which produces a therapeutic effect.Generally, out of one hundred percent, this amount will range from about0.1 percent to about ninety-nine percent of active ingredient,preferably from about 5 percent to about 70 percent, most preferablyfrom about 10 percent to about 30 percent.

In certain embodiments, a formulation of the present invention comprisesan excipient selected from the group consisting of cyclodextrins,celluloses, liposomes, micelle forming agents, e.g., bile acids, andpolymeric carriers, e.g., polyesters and polyanhydrides; and a compoundof the present invention. In certain embodiments, an aforementionedformulation renders orally bioavailable a compound of the presentinvention.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules, trouches and thelike), the active ingredient is mixed with one or morepharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, carboxymethylcellulose, alginates,gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants,such as glycerol; (4) disintegrating agents, such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate; (5) solution retarding agents, such as paraffin;(6) absorption accelerators, such as quaternary ammonium compounds andsurfactants, such as poloxamer and sodium lauryl sulfate; (7) wettingagents, such as, cetyl alcohol, glycerol monostearate, and non-ionicsurfactants; (8) absorbents, such as kaolin and bentonite clay; (9)lubricants, such as talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, zinc stearate, sodiumstearate, stearic acid, and mixtures thereof; (10) coloring agents; and(11) controlled-release agents, such as crospovidone or ethyl cellulose.In the case of capsules, tablets and pills, the pharmaceuticalcompositions may also comprise buffering agents. Solid compositions of asimilar type may also be employed as fillers in soft and hard-shelledgelatin capsules using such excipients as lactose or milk sugars, aswell as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be formulated for rapid release,e.g., freeze-dried. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedin sterile water, or some other sterile injectable medium immediatelybefore use. These compositions may also optionally contain opacifyingagents and may be of a composition that they release the activeingredient(s) only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable non-irritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically-acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the compoundin a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions prior to use, which may containsugars, alcohols, antioxidants, buffers, bacteriostats, solutes whichrender the formulation isotonic with the blood of the intended recipientor suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants, such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms upon the subject compounds may be ensuredby the inclusion of various antibacterial and antifungal agents, forexample, paraben, chlorobutanol, phenol sorbic acid, and the like. Itmay also be desirable to include isotonic agents, such as sugars, sodiumchloride, and the like into the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption, such as aluminummonostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This result may be accomplished by the use of a liquidsuspension of crystalline or amorphous material having poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of aparenterally-administered drug form is accomplished by dissolving orsuspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers, such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue.

When the compounds of the present invention are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99% (morepreferably, 10 to 30%) of active ingredient in combination with apharmaceutically acceptable carrier.

The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given in formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, administration by injection, infusion orinhalation; topical by lotion or ointment; and rectal by suppositories.

The phrases “parenteral administration” and “administered parenterally”as used herein mean modes of administration other than enteral andtopical administration, usually by injection, and include, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

Compounds may be administered to humans and other animals for therapy byany suitable route of administration, including orally, nasally, as by,for example, a spray, rectally, intravaginally, parenterally,intracisternally and topically, as by powders, ointments or drops,including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically-acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion ormetabolism of the particular compound being employed, the rate andextent of absorption, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Generally, oral, intravenous,intracerebroventricular and subcutaneous doses of the compounds of thisinvention for a patient, when used for the indicated effects, will rangefrom about 0.0001 to about 100 mg per kilogram of body weight per day.

Oral administration in humans is specifically contemplated by theinvention. Oral dosing in adult humans is typically on the order of 0.05grams (50 mg) to 10 grams per day, given as a single dose or in divideddoses. In one embodiment, oral dosing to adult humans is 0.5 grams (500mg) to 10 grams per day, given as a single dose or in divided doses. Inone embodiment, oral dosing to adult humans is 0.5 to 8 grams per day,given as a single dose or in divided doses. In one embodiment, oraldosing to adult humans is 0.5 to 6 grams per day, given as a single doseor in divided doses. In one embodiment, oral dosing to adult humans is0.5 to 4 grams per day, given as a single dose or in divided doses. Inone embodiment, oral dosing to adult humans is 0.5 to 2 grams per day,given as a single dose or in divided doses. In one embodiment, oraldosing to adult humans is 0.5 to 1 gram per day, given as a single doseor in divided doses.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. Exemplary dosing is one administrationper day.

While it is possible for a compound of the present invention to beadministered alone, it is preferable to administer the compound as apharmaceutical formulation (composition).

The compounds according to the invention may be formulated foradministration in any convenient way for use in human or veterinarymedicine, by analogy with other pharmaceuticals.

In another aspect, the present invention provides pharmaceuticallyacceptable compositions which comprise a therapeutically effectiveamount of one or more of the subject compounds, as described above,formulated together with one or more pharmaceutically acceptablecarriers (additives) and/or diluents. As described in detail below, thepharmaceutical compositions of the present invention may be speciallyformulated for administration in solid or liquid form, including thoseadapted for the following: (1) oral administration, for example,drenches (aqueous or non-aqueous solutions or suspensions), tablets,boluses, powders, granules, pastes for application to the tongue; (2)parenteral administration, for example, by subcutaneous, intramuscularor intravenous injection as, for example, a sterile solution orsuspension; (3) topical application, for example, as a cream, ointmentor spray applied to the skin, lungs, or mucous membranes; or (4)intravaginally or intrarectally, for example, as a pessary, cream orfoam; (5) sublingually or buccally; (6) ocularly; (7) transdermally; or(8) nasally.

The patient receiving this treatment is any animal in need, includingprimates, in particular humans, and other mammals, such as equines,cattle, swine and sheep; and poultry and pets in general.

The compound of the invention can be administered as such or inadmixtures with pharmaceutically acceptable carriers and can also beadministered in conjunction with at least one other active compound.Conjunctive therapy thus includes sequential, simultaneous and separateadministration of the active compound in a way that the therapeuticaleffects of the first administered one is not entirely disappeared whenthe subsequent is administered.

Micelles.

Microemulsification technology improves bioavailability of somelipophilic (water insoluble) pharmaceutical agents. Examples includeTrimetrine (Dordunoo, S. K., et al., Drug Development and IndustrialPharmacy, 17(12), 1685-1713, 1991 and REV 5901 (Sheen, P. C., et al., JPharm Sci 80(7), 712-714, 1991). Among other things, microemulsificationprovides enhanced bioavailability by preferentially directing absorptionto the lymphatic system instead of the circulatory system, which therebybypasses the liver, and prevents destruction of the compounds in thehepatobiliary circulation.

While all suitable amphiphilic carriers are contemplated, exemplarycarriers are generally those that have Generally-Recognized-as-Safe(GRAS) status, and that can both solubilize the compound of the presentinvention and microemulsify it at a later stage when the solution comesinto a contact with a complex water phase (such as one found in humangastro-intestinal tract). Usually, amphiphilic ingredients that satisfythese requirements have HLB (hydrophilic to lipophilic balance) valuesof 2-20, and their structures contain straight chain aliphatic radicalsin the range of C-6 to C-20. Examples are polyethylene-glycolized fattyglycerides and polyethylene glycols.

Commercially available amphiphilic carriers are particularlycontemplated, including Gelucire-series, Labrafil, Labrasol, orLauroglycol (all manufactured and distributed by Gattefosse Corporation,Saint Priest, France), PEG-mono-oleate, PEG-di-oleate, PEG-mono-laurateand di-laurate, Lecithin, Polysorbate 80, etc (produced and distributedby a number of companies in USA and worldwide).

Polymers.

Hydrophilic polymers suitable for use in the present invention are thosewhich are readily water-soluble, can be covalently attached to avesicle-forming lipid, and which are tolerated in vivo without toxiceffects (i.e., are biocompatible). Suitable polymers includepolyethylene glycol (PEG), polylactic (also termed polylactide),polyglycolic acid (also termed polyglycolide), a polylactic-polyglycolicacid copolymer, and polyvinyl alcohol. Exemplary polymers are thosehaving a molecular weight of from about 100 or 120 Daltons up to about5,000 or 10,000 Daltons, and more preferably from about 300 Daltons toabout 5,000 Daltons. In one embodiment, the polymer ispolyethyleneglycol having a molecular weight of from about 100 to about5,000 Daltons, and more preferably having a molecular weight of fromabout 300 to about 5,000 Daltons. In one embodiment, the polymer ispolyethyleneglycol of 750 Daltons (PEG(750)). Polymers may also bedefined by the number of monomers therein; an embodiment of the presentinvention utilizes polymers of at least about three monomers, such PEGpolymers consisting of three monomers (approximately 150 Daltons).

Other hydrophilic polymers which may be suitable for use in the presentinvention include polyvinylpyrrolidone, polymethoxazoline,polyethyloxazoline, polyhydroxypropyl methacrylamide,polymethacrylamide, polydimethylacrylamide, and derivatized cellulosessuch as hydroxymethylcellulose or hydroxyethylcellulose.

In certain embodiments, a formulation of the present invention comprisesa biocompatible polymer selected from the group consisting ofpolyamides, polycarbonates, polyalkylenes, polymers of acrylic andmethacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes,polyurethanes and co-polymers thereof, celluloses, polypropylene,polyethylenes, polystyrene, polymers of lactic acid and glycolic acid,polyanhydrides, poly(ortho)esters, poly(butic acid), poly(valeric acid),poly(lactide-co-caprolactone), polysaccharides, proteins, polyhyaluronicacids, polycyanoacrylates, and blends, mixtures, or copolymers thereof.

Cyclodextrins.

Cyclodextrins are cyclic oligosaccharides, consisting of 6, 7 or 8glucose units, designated by the Greek letters alpha, beta and gamma,respectively. The glucose units are linked by alpha-1,4-glucosidicbonds. As a consequence of the chair conformation of the sugar units,all secondary hydroxyl groups (at C-2, C-3) are located on one side ofthe ring, while all the primary hydroxyl groups at C-6 are situated onthe other side. As a result, the external faces are hydrophilic, makingthe cyclodextrins water-soluble. In contrast, the cavities of thecyclodextrins are hydrophobic, since they are lined by the hydrogen ofatoms C-3 and C-5, and by ether-like oxygens. These matrices allowcomplexation with a variety of relatively hydrophobic compounds,including, for instance, steroid compounds such as 17-beta-estradiol(see, e.g., van Uden et al. Plant Cell Tiss. Org. Cult. 38:1-3-113(1994)). The complexation takes place by Van der Waals interactions andby hydrogen bond formation. For a general review of the chemistry ofcyclodextrins, see, Wenz, Agnew. Chem. Int. Ed. Engl., 33:803-822(1994).

The physico-chemical properties of the cyclodextrin derivatives dependstrongly on the kind and the degree of substitution. For example, theirsolubility in water ranges from insoluble (e.g.,triacetyl-beta-cyclodextrin) to 147% soluble (w/v)(G-2-beta-cyclodextrin). In addition, they are soluble in many organicsolvents. The properties of the cyclodextrins enable the control oversolubility of various formulation components by increasing or decreasingtheir solubility.

Numerous cyclodextrins and methods for their preparation have beendescribed. For example, Parmeter (I), et al. (U.S. Pat. No. 3,453,259;incorporated by reference) and Gramera, et al. (U.S. Pat. No. 3,459,731;incorporated by reference) describe electroneutral cyclodextrins. Otherderivatives include cyclodextrins with cationic properties (Parmeter(II), U.S. Pat. No. 3,453,257; incorporated by reference), insolublecrosslinked cyclodextrins (Solms, U.S. Pat. No. 3,420,788; incorporatedby reference), and cyclodextrins with anionic properties (Parmeter(III), U.S. Pat. No. 3,426,011; incorporated by reference). Among thecyclodextrin derivatives with anionic properties, carboxylic acids,phosphorous acids, phosphinous acids, phosphonic acids, phosphoricacids, thiophosphonic acids, thiosulphinic acids, and sulfonic acidshave been appended to the parent cyclodextrin (see, Parmeter (III),supra). Furthermore, sulfoalkyl ether cyclodextrin derivatives have beendescribed by Stella, et al. (U.S. Pat. No. 5,134,127; incorporated byreference).

Liposomes.

Liposomes consist of at least one lipid bilayer membrane enclosing anaqueous internal compartment. Liposomes may be characterized by membranetype and by size. Small unilamellar vesicles (SUVs) have a singlemembrane and typically range between 0.02 and 0.05 μm in diameter; largeunilamellar vesicles (LUVS) are typically larger than 0.05 μm.Oligolamellar large vesicles and multilamellar vesicles have multiple,usually concentric, membrane layers and are typically larger than 0.1μm. Liposomes with several nonconcentric membranes, i.e., severalsmaller vesicles contained within a larger vesicle, are termedmultivesicular vesicles.

One aspect of the present invention relates to formulations comprisingliposomes containing a compound of the present invention, where theliposome membrane is formulated to provide a liposome with increasedcarrying capacity. Alternatively or in addition, the compound of thepresent invention may be contained within, or adsorbed onto, theliposome bilayer of the liposome. The compound of the present inventionmay be aggregated with a lipid surfactant and carried within theliposome's internal space; in these cases, the liposome membrane isformulated to resist the disruptive effects of the activeagent-surfactant aggregate.

According to one embodiment of the present invention, the lipid bilayerof a liposome contains lipids derivatized with polyethylene glycol(PEG), such that the PEG chains extend from the inner surface of thelipid bilayer into the interior space encapsulated by the liposome, andextend from the exterior of the lipid bilayer into the surroundingenvironment.

Active agents contained within liposomes of the present invention are insolubilized form. Aggregates of surfactant and active agent (such asemulsions or micelles containing the active agent of interest) may beentrapped within the interior space of liposomes according to thepresent invention. A surfactant acts to disperse and solubilize theactive agent, and may be selected from any suitable aliphatic,cycloaliphatic or aromatic surfactant, including but not limited tobiocompatible lysophosphatidylcholines (LPCs) of varying chain lengths(for example, from about C14 to about C20). Polymer-derivatized lipidssuch as PEG-lipids may also be utilized for micelle formation as theywill act to inhibit micelle/membrane fusion, and as the addition of apolymer to surfactant molecules decreases the critical micelleconcentration (CMC) of the surfactant and aids in micelle formation.Examples are surfactants with CMCs in the micromolar range; higher CMCsurfactants may be utilized to prepare micelles entrapped withinliposomes of the present invention, however, micelle surfactant monomerscould affect liposome bilayer stability and would be a factor indesigning a liposome of a desired stability.

Liposomes useful in the present invention may be prepared by any of avariety of techniques that are known in the art. See, e.g., U.S. Pat.No. 4,235,871; Published PCT applications WO 96/14057; New R R C,Liposomes: A practical approach, IRL Press, Oxford (1990), pages 33-104;Lasic D D, Liposomes from physics to applications, Elsevier SciencePublishers BV, Amsterdam, 1993.

For example, liposomes useful in the present invention may be preparedby diffusing a lipid derivatized with a hydrophilic polymer intopreformed liposomes, such as by exposing preformed liposomes to micellescomposed of lipid-grafted polymers, at lipid concentrationscorresponding to the final mole percent of derivatized lipid which isdesired in the liposome. Liposomes containing a hydrophilic polymer canalso be formed by homogenization, lipid-field hydration, or extrusiontechniques, as are known in the art.

In one aspect of the present invention, the liposomes have substantiallyhomogeneous sizes in a selected size range. One effective sizing methodinvolves extruding an aqueous suspension of the liposomes through aseries of polycarbonate membranes having a selected uniform pore size;the pore size of the membrane will correspond roughly with the largestsizes of liposomes produced by extrusion through that membrane. Seee.g., U.S. Pat. No. 4,737,323.

Release Modifiers.

The release characteristics of a formulation of the present inventiondepend on the encapsulating material, the concentration of encapsulateddrug, and the presence of release modifiers. For example, release can bemanipulated to be pH dependent using a pH sensitive coating thatreleases only at a low pH, as in the stomach, or a higher pH, as in theintestine. An enteric coating can be used to prevent release fromoccurring until after passage through the stomach. Multiple coatings ormixtures of cyanamide encapsulated in different materials can be used toobtain an initial release in the stomach, followed by later release inthe intestine. Release can also be manipulated by inclusion of salts orpore forming agents, which can increase water uptake or release of drugby diffusion from the capsule. Excipients which modify the solubility ofthe drug can also be used to control the release rate. Agents whichenhance degradation of the matrix or release from the matrix can also beincorporated. They can be added to the drug, added as a separate phase(i.e., as particulates), or can be co-dissolved in the polymer phasedepending on the compound. In all cases the amount should be between 0.1and thirty percent (w/w polymer). Types of degradation enhancers includeinorganic salts, such as ammonium sulfate and ammonium chloride, organicacids, such as citric acid, benzoic acid, and ascorbic acid, inorganicbases, such as sodium carbonate, potassium carbonate, calcium carbonate,zinc carbonate, and zinc hydroxide, and organic bases, such as protaminesulfate, spermine, choline, ethanolamine, diethanolamine, andtriethanolamine and surfactants, such as Tween® and Pluronic®. Poreforming agents which add microstructure to the matrices (i.e., watersoluble compounds, such as inorganic salts and sugars) are added asparticulates. The range should be between one and thirty percent (w/wpolymer).

Uptake can also be manipulated by altering residence time of theparticles in the gut. This can be achieved, for example, by coating theparticle with, or selecting as the encapsulating material, a mucosaladhesive polymer. Examples include most polymers with free carboxylgroups, such as chitosan, celluloses, and especially polyacrylates (asused herein, polyacrylates refers to polymers including acrylate groupsand modified acrylate groups such as cyanoacrylates and methacrylates).

One aspect of the invention relates to a pharmaceutical composition,comprising a compound of the present invention or a pharmaceuticallyacceptable salt thereof; and a pharmaceutically acceptable excipient.

In certain embodiments, the present invention relates to any one of theaforementioned pharmaceutical compositions, wherein the pharmaceuticalpreparation has an EC₅₀ for reducing serum cholesterol, LDL and/ortriglycerides which, in the average human patient population, is no morethan 20 percent of the half maximal concentration of pharmaceuticalpreparation which would cause cutaneous vasodilation (flushing) in theaverage patient population.

In certain embodiments, the present invention relates to any one of theaforementioned pharmaceutical compositions, wherein the EC₅₀ forreducing serum cholesterol, LDL and/or triglycerides is no more than 1percent of the half maximal concentration of pharmaceutical preparationwhich would cause cutaneous vasodilation (flushing) in the averagepatient population.

In certain embodiments, the present invention relates to any one of theaforementioned pharmaceutical compositions, wherein the pharmaceuticalpreparation has an EC₅₀ for reducing serum cholesterol, LDL and/ortriglycerides which, in the average human patient population, is no morethan 20 percent of the concentration of pharmaceutical preparation whichwould cause increases in serum levels of aspartate aminotransferase(AST) and alanine aminotransferase (ALT) requiring discontinuation ofadministration of the pharmaceutical preparation.

In certain embodiments, the present invention relates to any one of theaforementioned pharmaceutical compositions, wherein said composition iseffective in reducing a serum lipid without causing treatment-limiting(i) hepatotoxicity and (ii) elevations in uric acid levels or glucoselevels or both, following administration to said patient that wouldrequire such treatment to be discontinued when said composition isingested by said patient once per day.

In certain embodiments, the present invention relates to any one of theaforementioned pharmaceutical compositions formulated in combinationwith a statin.

In certain embodiments, the present invention relates to any one of theaforementioned pharmaceutical compositions, wherein the statin isselected from the group consisting of atorvastatin, cerivastatin,fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin,rosuvastatin and simvastatin.

In certain embodiments, the present invention relates to any one of theaforementioned pharmaceutical compositions formulated in combinationwith at least one additional therapeutic agent selected from the groupconsisting of 11β HSD-1 inhibitors, 5HT transporter inhibitors, 5HT2cagonists, 5-LO or FLAP inhibitors, α-glucosidase inhibitors, ABCA1enhancers, ACC inhibitors, AcylCoA:cholesterol O-acyltransferaseinhibitors, acyl-estrogens, antidiabetic agents, anti-dyslipidemicagents, anti-hypertensive agents, antioxidants, Apo A1 mimetics, Apo A1modulators, Apo E mimetics, apolipoprotein-B secretion/microsomaltriglyceride transfer protein (apo-B/MTP) inhibitors, appetitesuppressants, aspirin, β3 agonists, bile acid reabsorption inhibitors,bile acid sequestrants, bombesin agonists, BRS3 agonists, CB₁antagonists/inverse agonists, CCK-A agonists, cholesterol absorptioninhibitor, cholesterol transport inhibitors, cholesteryl ester transferprotein (CETP) inhibitors, CNTF, CNTF agonists/modulators, a combinationof ezetimibe and simvastatin and/or atorvastatin, CSL-111,dehydroepiandrosterone, delipidated HDL, DGAT antisense oligos, DGAT1inhibitors, DGAT2 inhibitors, dicarboxylate transporter inhibitors,dopamine agonists, DP receptor antagonists, ezetimibe, FAS inhibitors,fatty acid binding protein (FABP) inhibitors, fatty acid transporterinhibitors, fatty acid transporter protein (FATP) inhibitors, flushinhibitors, FXR receptor modulators, galanin receptor antagonists,gemcabene, ghrelin antagonists, ghrelin antibodies, GLP-1 agonists,glucagon-like peptide-1 receptor agonists, glucocorticoidagonists/antagonists, glucose transporter inhibitors, HDL mimetics, HMGCoA reductase inhibitor compounds, HMG-CoA synthetase inhibitors,hormone sensitive lipase antagonists, human agouti-related proteins(AGRP), H₃ antagonists/inverse agonists, inorganic cholesterolsequestrants, L-4f, lapaquistat, leptin agonists/modulators, leptins,lipase inhibitors, lipoprotein synthesis inhibitors, lorapoprant, lowdensity lipoprotein receptor inducers or activators, Lp(a) reducers, LXRreceptor agonists, lyn kinase inhibitor, Mc3r agonists, Mc4r agonists,MCH1R antagonists, MCH2R agonists/antagonists, melanin concentratinghormone antagonists, mGluR5 antagonists, microsomal triglyceridetransport inhibitors, monoamine reuptake inhibitors, natural watersoluble fibers, NE transporter inhibitors, neuromedin U receptoragonists, neuropeptide-Y antagonists, niacin or niacin receptoragonists, nicotinic acid, noradrenergic anorectic agents, NPY1antagonists, NPY2 agonists, NPY4 agonists, NPY5 antagonists,non-steroidal anti-inflammatory drug (NSAID) agents, omega-3 fattyacids, opioid antagonists, orexin receptor antagonists, PDE inhibitors,phentermine, phosphate transporter inhibitors, phytopharm compound 57,plant stanols and/or fatty acid esters of plant stanols, plateletaggregation inhibitors, PPAR-α agonists, PPAR-δ agonists, PPAR-δ partialagonists, PPAR-γ agonists, probucol, renin angiotensin inhibitors,reversed-4F, SCD-1 inhibitors, serotonin reuptake inhibitors, SGLT2inhibitors, squalene epoxidase inhibitors, squalene synthesisinhibitors, sterol biosynthesis inhibitors, sympathomimetic agonists,thyroid hormone 13 agonists, thyromimetic agents, topiramate,triglyceride synthesis inhibitors, UCP-1 activators, UCP-2 activators,UCP-3 activators, and urocortin binding protein antagonists.

In certain embodiments, the present invention relates to apharmaceutical composition, comprising a compound of the presentinvention or a pharmaceutically acceptable salt thereof; niacin; and apharmaceutically acceptable excipient.

In certain embodiments, the present invention relates to apharmaceutical composition, comprising a compound of the presentinvention or a pharmaceutically acceptable salt thereof; niacin; astatin selected from the group consisting of atorvastatin, cerivastatin,fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin,rosuvastatin and simvastatin; and a pharmaceutically acceptableexcipient.

In certain embodiments, the present invention relates to apharmaceutical composition, comprising a compound of the presentinvention or a pharmaceutically acceptable salt thereof; a glitazoneselected from the group consisting of troglitazone, rosiglitazone, andpioglitazone; and a pharmaceutically acceptable excipient.

In certain embodiments, the present invention relates to apharmaceutical composition, comprising a compound of the presentinvention or a pharmaceutically acceptable salt thereof; niacin; aglitazone selected from the group consisting of troglitazone,rosiglitazone, and pioglitazone; and a pharmaceutically acceptableexcipient.

In certain embodiments, the present invention relates to apharmaceutical composition, comprising a compound of the presentinvention or a pharmaceutically acceptable salt thereof; a fibrateselected from the group consisting of fenofibrate and bezafibrate; and apharmaceutically acceptable excipient.

In certain embodiments, the present invention relates to apharmaceutical composition, comprising a compound of the presentinvention or a pharmaceutically acceptable salt thereof; niacin; afibrate selected from the group consisting of fenofibrate andbezafibrate; and a pharmaceutically acceptable excipient.

Methods

An aspect of the invention relates to a method of treating a disease,disorder, or condition selected from the group consisting ofhyperlipidemia, hypercholesterolemia, lipodystrophy, dyslipidemia,atherosclerosis and coronary artery disease, comprising the step ofadministering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention or a pharmaceuticallyacceptable salt thereof. In one embodiment, the mammal is a human.

An aspect of the invention relates to a method of treating a disease,disorder, or condition selected from the group consisting ofhyperlipidemia, hypercholesterolemia, lipodystrophy, dyslipidemia,atherosclerosis and coronary artery disease, comprising the step ofadministering to a mammal in need thereof a therapeutically effectiveamount of a pharmaceutical composition of the present invention. In oneembodiment, the mammal is a human.

An aspect of the invention relates to a method of treating a disease,disorder, or condition selected from the group consisting of metabolicsyndrome, obesity, fatty liver disease, and diabetes, comprising thestep of administering to a mammal in need thereof a therapeuticallyeffective amount of a compound of the present invention or apharmaceutically acceptable salt thereof. In one embodiment, the mammalis a human.

An aspect of the invention relates to a method of treating a disease,disorder, or condition selected from the group consisting of metabolicsyndrome, obesity, fatty liver disease, and diabetes, comprising thestep of administering to a mammal in need thereof a therapeuticallyeffective amount of a pharmaceutical composition of the presentinvention. In one embodiment, the mammal is a human.

An aspect of the invention relates to a method of raising serumhigh-density lipoprotein (HDL) levels, comprising the step of:administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention or a pharmaceuticallyacceptable salt thereof. In one embodiment, the mammal is a human.

An aspect of the invention relates to a method of raising serumhigh-density lipoprotein (HDL) levels, comprising the step of:administering to a mammal in need thereof a therapeutically effectiveamount of a pharmaceutical composition of the present invention. In oneembodiment, the mammal is a human.

An aspect of the invention relates to a method of lowering serumlow-density lipoprotein (LDL) levels or lowering serum lipoprotein (a)levels, comprising the step of administering to a mammal in need thereofa therapeutically effective amount of a compound of the presentinvention or a pharmaceutically acceptable salt thereof. In oneembodiment, the mammal is a human.

An aspect of the invention relates to a method of lowering serumlow-density lipoprotein (LDL) levels or lowering serum lipoprotein (a)levels, comprising the step of administering to a mammal in need thereofa therapeutically effective amount of a pharmaceutical composition ofthe present invention. In one embodiment, the mammal is a human.

An aspect of the invention relates to a method of treating a disease,disorder, or condition selected from the group consisting of congestiveheart failure, cardiovascular disease, hypertension, coronary heartdisease, angina, pellagra, Hartnup's syndrome, carcinoid syndrome,arterial occlusive disease, hypothyroidism, vasoconstriction,osteoarthritis, rheumatoid arthritis, Alzheimer's disease, disorders ofthe peripheral and central nervous system, hematological diseases,cancer, inflammation, respiratory diseases, and gastroenterologicaldiseases, comprising the step of administering to a mammal in needthereof a compound of the present invention or a pharmaceuticallyacceptable salt thereof. In one embodiment, the mammal is a human.

An aspect of the invention relates to a method of treating a disease,disorder, or condition selected from the group consisting of congestiveheart failure, cardiovascular disease, hypertension, coronary heartdisease, angina, pellagra, Hartnup's syndrome, carcinoid syndrome,arterial occlusive disease, hypothyroidism, vasoconstriction,osteoarthritis, rheumatoid arthritis, Alzheimer's disease, disorders ofthe peripheral and central nervous system, hematological diseases,cancer, inflammation, respiratory diseases, and gastroenterologicaldiseases, comprising the step of administering to a mammal in needthereof a pharmaceutical composition of the present invention. In oneembodiment, the mammal is a human.

In certain embodiments, the present invention relates to any one of theaforementioned methods, further comprising co-administering atherapeutically effective amount of a statin. In one such embodiment,the co-administering is co-administering orally.

In certain embodiments, the present invention relates to any one of theaforementioned methods, further comprising co-administering atherapeutically effective amount of a statin; wherein the statin isselected from the group consisting of atorvastatin, cerivastatin,fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin,rosuvastatin and simvastatin. In one such embodiment, theco-administering is co-administering orally.

In certain embodiments, the present invention relates to any one of theaforementioned methods, further comprising co-administering atherapeutically effective amount of at least one additional therapeuticagent selected from the group consisting of 11β HSD-1 inhibitors, 5HTtransporter inhibitors, 5HT2c agonists, 5-LO or FLAP inhibitors,α-glucosidase inhibitors, ABCA1 enhancers, ACC inhibitors,AcylCoA:cholesterol O-acyltransferase inhibitors, acyl-estrogens,antidiabetic agents, anti-dyslipidemic agents, anti-hypertensive agents,anti-oxidants, Apo A1 mimetics, Apo A1 modulators, Apo E mimetics,apolipoprotein-B secretion/microsomal triglyceride transfer protein(apo-B/MTP) inhibitors, appetite suppressants, aspirin, β3 agonists,bile acid reabsorption inhibitors, bile acid sequestrants, bombesinagonists, BRS3 agonists, CB₁ antagonists/inverse agonists, CCK-Aagonists, cholesterol absorption inhibitor, cholesterol transportinhibitors, cholesteryl ester transfer protein (CETP) inhibitors, CNTF,CNTF agonists/modulators, a combination of ezetimibe and simvastatinand/or atorvastatin, CSL-111, dehydroepiandrosterone, delipidated HDL,DGAT antisense oligos, DGAT1 inhibitors, DGAT2 inhibitors, dicarboxylatetransporter inhibitors, dopamine agonists, DP receptor antagonists,ezetimibe, FAS inhibitors, fatty acid binding protein (FABP) inhibitors,fatty acid transporter inhibitors, fatty acid transporter protein (FATP)inhibitors, flush inhibitors, FXR receptor modulators, galanin receptorantagonists, gemcabene, ghrelin antagonists, ghrelin antibodies, GLP-1agonists, glucagon-like peptide-1 receptor agonists, glucocorticoidagonists/antagonists, glucose transporter inhibitors, HDL mimetics, HMGCoA reductase inhibitor compounds, HMG-CoA synthetase inhibitors,hormone sensitive lipase antagonists, human agouti-related proteins(AGRP), H₃ antagonists/inverse agonists, inorganic cholesterolsequestrants, L-4f, lapaquistat, leptin agonists/modulators, leptins,lipase inhibitors, lipoprotein synthesis inhibitors, lorapoprant, lowdensity lipoprotein receptor inducers or activators, Lp(a) reducers, LXRreceptor agonists, lyn kinase inhibitor, Mc3r agonists, Mc4r agonists,MCH1R antagonists, MCH2R agonists/antagonists, melanin concentratinghormone antagonists, mGluR5 antagonists, microsomal triglyceridetransport inhibitors, monoamine reuptake inhibitors, natural watersoluble fibers, NE transporter inhibitors, neuromedin U receptoragonists, neuropeptide-γ antagonists, niacin or niacin receptoragonists, nicotinic acid, noradrenergic anorectic agents, NPY1antagonists, NPY2 agonists, NPY4 agonists, NPY5 antagonists,non-steroidal anti-inflammatory drug (NSAID) agents, omega-3 fattyacids, opioid antagonists, orexin receptor antagonists, PDE inhibitors,phentermine, phosphate transporter inhibitors, phytopharm compound 57,plant stanols and/or fatty acid esters of plant stanols, plateletaggregation inhibitors, PPAR-α agonists, PPAR-δ agonists, PPAR-δ partialagonists, PPAR-γ agonists, probucol, renin angiotensin inhibitors,reversed-4F, SCD-1 inhibitors, serotonin reuptake inhibitors, SGLT2inhibitors, squalene epoxidase inhibitors, squalene synthesisinhibitors, sterol biosynthesis inhibitors, sympathomimetic agonists,thyroid hormone β agonists, thyromimetic agents, topiramate,triglyceride synthesis inhibitors, UCP-1 activators, UCP-2 activators,UCP-3 activators, and urocortin binding protein antagonists. In one suchembodiment, the co-administering is co-administering orally.

In certain embodiments, the present invention relates to any one of theaforementioned methods, further comprising co-administering atherapeutically effective amount of at least one additional therapeuticagent selected from the group consisting of HMG CoA reductaseinhibitors, aspirin, cholesteryl ester transfer protein inhibitors,NSAIDs, fibrates, a proprotein convertase subtilisin/kexin type (PCSK9),inorganic cholesterol sequestrants, AcylCoA:cholesterolO-acyltransferase inhibitors, CETP inhibitors, PPAR α agonists, PPAR γagonists, bile acid reabsorption inhibitors, triglyceride synthesisinhibitors, lipoprotein receptor activators, DGAT1 inhibitors, SCD-1inhibitors, lipase inhibitors, DP receptor antagonists, apo A1modulators, cholesterol transport inhibitors, metformin, niacin receptormodulators, and DPP-IV inhibitors. In one such embodiment, theco-administering is co-administering orally.

In certain embodiments, the present invention relates to any one of theaforementioned methods, further comprising co-administering atherapeutically effective amount of at least one additional therapeuticagent selected from the group consisting of HMG CoA reductaseinhibitors, cholesteryl ester transfer protein inhibitors, aspirin,NSAIDs, fibrates, DP receptor antagonists, ezetimibe or a combination ofezetimibe and simvastatin. In one such embodiment, the co-administeringis co-administering orally.

In certain embodiments, the present invention relates to any one of theaforementioned methods, further comprising co-administering atherapeutically effective amount of at least one HMG CoA reductaseinhibitor selected from lovastatin, simvastatin, pravastatin,atorvastatin, fluvastatin, cerivastatin, rivastatin, rosuvastatincalcium and pitavastatin. In one such embodiment, the co-administeringis co-administering orally.

In certain embodiments, the present invention relates to any one of theaforementioned methods, further comprising co-administering simvastatin.In one such embodiment, the co-administering is co-administering orally.

In certain embodiments, the present invention relates to any one of theaforementioned methods, further comprising co-administering acholesteryl ester transfer protein inhibitor. In one such embodiment,the co-administering is co-administering orally.

In certain embodiments, the present invention relates to any one of theaforementioned methods, further comprising co-administering ezetimibe,aspirin, ibuprofen, acetaminophen, or a combination of ezetimibe andsimvastatin. In one such embodiment, the co-administering isco-administering orally.

An aspect of the invention relates to a method of treatinghyperlipidemia, comprising the step of co-administering to a mammal inneed thereof a therapeutically effective amount of a compound of thepresent invention; and a therapeutically effective amount of niacin. Inone embodiment, the co-administering is co-administering orally. In oneembodiment, the mammal is a human.

An aspect of the invention relates to a method of treatinghyperlipidemia, comprising the step of co-administering to a mammal inneed thereof a therapeutically effective amount of a pharmaceuticalcomposition of the present invention; and a therapeutically effectiveamount of niacin. In one embodiment, the co-administering isco-administering orally. In one embodiment, the mammal is a human.

An aspect of the invention relates to a method of raising serumhigh-density lipoprotein (HDL) levels in a mammal, comprising the stepof co-administering to a mammal in need thereof a therapeuticallyeffective amount of a compound of the present invention; and atherapeutically effective amount of niacin. In one embodiment, theco-administering is co-administering orally. In one embodiment, themammal is a human.

An aspect of the invention relates to a method of raising serumhigh-density lipoprotein (HDL) levels in a mammal, comprising the stepof co-administering to a mammal in need thereof a therapeuticallyeffective amount of a pharmaceutical composition of the presentinvention; and a therapeutically effective amount of niacin. In oneembodiment, the co-administering is co-administering orally. In oneembodiment, the mammal is a human.

An aspect of the invention relates to a method of lowering serumlow-density lipoprotein (LDL) levels in a mammal, comprising the step ofco-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention; and a therapeuticallyeffective amount of niacin. In one embodiment, the co-administering isco-administering orally. In one embodiment, the mammal is a human.

An aspect of the invention relates to a method of lowering serumlow-density lipoprotein (LDL) levels in a mammal, comprising the step ofco-administering to a mammal in need thereof a therapeutically effectiveamount of a pharmaceutical composition of the present invention; and atherapeutically effective amount of niacin. In one embodiment, theco-administering is co-administering orally. In one embodiment, themammal is a human.

An aspect of the invention relates to a method of lowering serumlipoprotein (a) (Lp(a)) levels in a mammal, comprising the step ofco-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention; and a therapeuticallyeffective amount of niacin. In one embodiment, the co-administering isco-administering orally. In one embodiment, the mammal is a human.

An aspect of the invention relates to a method of lowering serumlipoprotein (a) (Lp(a)) levels in a mammal, comprising the step ofco-administering to a mammal in need thereof a therapeutically effectiveamount of a pharmaceutical composition of the present invention; and atherapeutically effective amount of niacin. In one embodiment, theco-administering is co-administering orally. In one embodiment, themammal is a human.

An aspect of the invention relates to a method of treatinghyperlipidemia, hypercholesterolemia, atherosclerosis, coronary arterydisease, congestive heart failure, cardiovascular disease, hypertension,coronary heart disease, angina, pellagra, Hartnup's syndrome, carcinoidsyndrome, arterial occlusive disease, obesity, hypothyroidism,vasoconstriction, osteoarthritis, rheumatoid arthritis, diabetes,Alzheimer's disease, lipodystrophy, or dyslipidemia, comprising the stepof co-administering to a mammal in need thereof a therapeuticallyeffective amount of a compound of the present invention; atherapeutically effective amount of niacin; and a therapeuticallyeffective amount of a statin selected from the group consisting ofatorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,pitavastatin, pravastatin, rosuvastatin and simvastatin. In oneembodiment, the co-administering is co-administering orally. In oneembodiment, the mammal is a human.

An aspect of the invention relates to a method of treatinghyperlipidemia, hypercholesterolemia, atherosclerosis, coronary arterydisease, congestive heart failure, cardiovascular disease, hypertension,coronary heart disease, angina, pellagra, Hartnup's syndrome, carcinoidsyndrome, arterial occlusive disease, obesity, hypothyroidism,vasoconstriction, osteoarthritis, rheumatoid arthritis, diabetes,Alzheimer's disease, lipodystrophy, or dyslipidemia, comprising the stepof co-administering to a mammal in need thereof a therapeuticallyeffective amount of a pharmaceutical composition of the presentinvention; a therapeutically effective amount of niacin; and atherapeutically effective amount of a statin selected from the groupconsisting of atorvastatin, cerivastatin, fluvastatin, lovastatin,mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. Inone embodiment, the co-administering is co-administering orally. In oneembodiment, the mammal is a human.

An aspect of the invention relates to a method of treatinghyperlipidemia, comprising the step of co-administering to a mammal inneed thereof a therapeutically effective amount of a compound of thepresent invention; a therapeutically effective amount of niacin; and atherapeutically effective amount of a statin selected from the groupconsisting of atorvastatin, cerivastatin, fluvastatin, lovastatin,mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. Inone embodiment, the co-administering is co-administering orally. In oneembodiment, the mammal is a human.

An aspect of the invention relates to a method of treatinghyperlipidemia, comprising the step of co-administering to a mammal inneed thereof a therapeutically effective amount of a pharmaceuticalcomposition of the present invention; a therapeutically effective amountof niacin; and a therapeutically effective amount of a statin selectedfrom the group consisting of atorvastatin, cerivastatin, fluvastatin,lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin andsimvastatin. In one embodiment, the co-administering is co-administeringorally. In one embodiment, the mammal is a human.

An aspect of the invention relates to a method of raising serumhigh-density lipoprotein (HDL) levels in a mammal, comprising the stepof co-administering to a mammal in need thereof a therapeuticallyeffective amount of a compound of the present invention; atherapeutically effective amount of niacin; and a therapeuticallyeffective amount of a statin selected from the group consisting ofatorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,pitavastatin, pravastatin, rosuvastatin and simvastatin. In oneembodiment, the co-administering is co-administering orally. In oneembodiment, the mammal is a human.

An aspect of the invention relates to a method of raising serumhigh-density lipoprotein (HDL) levels in a mammal, comprising the stepof co-administering to a mammal in need thereof a therapeuticallyeffective amount of a pharmaceutical composition of the presentinvention; a therapeutically effective amount of niacin; and atherapeutically effective amount of a statin selected from the groupconsisting of atorvastatin, cerivastatin, fluvastatin, lovastatin,mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. Inone embodiment, the co-administering is co-administering orally. In oneembodiment, the mammal is a human.

An aspect of the invention relates to a method of lowering serumlow-density lipoprotein (LDL) levels in a mammal, comprising the step ofco-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention; a therapeuticallyeffective amount of niacin; and a therapeutically effective amount of astatin selected from the group consisting of atorvastatin, cerivastatin,fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin,rosuvastatin and simvastatin. In one embodiment, the co-administering isco-administering orally. In one embodiment, the mammal is a human.

An aspect of the invention relates to a method of lowering serumlow-density lipoprotein (LDL) levels in a mammal, comprising the step ofco-administering to a mammal in need thereof a therapeutically effectiveamount of a pharmaceutical composition of the present invention; atherapeutically effective amount of niacin; and a therapeuticallyeffective amount of a statin selected from the group consisting ofatorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,pitavastatin, pravastatin, rosuvastatin and simvastatin. In oneembodiment, the co-administering is co-administering orally. In oneembodiment, the mammal is a human.

An aspect of the invention relates to a method of lowering serumlipoprotein (a) (Lp(a)) levels in a mammal, comprising the step ofco-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention; a therapeuticallyeffective amount of niacin; and a therapeutically effective amount of astatin selected from the group consisting of atorvastatin, cerivastatin,fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin,rosuvastatin and simvastatin. In one embodiment, the co-administering isco-administering orally. In one embodiment, the mammal is a human.

An aspect of the invention relates to a method of lowering serumlipoprotein (a) (Lp(a)) levels in a mammal, comprising the step ofco-administering to a mammal in need thereof a therapeutically effectiveamount of a pharmaceutical composition of the present invention; atherapeutically effective amount of niacin; and a therapeuticallyeffective amount of a statin selected from the group consisting ofatorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,pitavastatin, pravastatin, rosuvastatin and simvastatin. In oneembodiment, the co-administering is co-administering orally. In oneembodiment, the mammal is a human.

In certain embodiments, the present invention relates to any one of theaforementioned methods and the attendant limitations, wherein saidstatin is lovastatin or atorvastatin.

An aspect of the invention relates to a method of treating diabetes in amammal, comprising the step of co-administering to a mammal in needthereof a therapeutically effective amount of a compound of the presentinvention or a pharmaceutically acceptable salt thereof; and a glitazoneselected from the group consisting of troglitazone, rosiglitazone, andpioglitazone. In one embodiment, the co-administering isco-administering orally. In one embodiment, the mammal is a human.

An aspect of the invention relates to a method of treating diabetes in amammal, comprising the step of co-administering to a mammal in needthereof a therapeutically effective amount of a pharmaceuticalcomposition of the present invention; and a glitazone selected from thegroup consisting of troglitazone, rosiglitazone, and pioglitazone. Inone embodiment, the co-administering is co-administering orally. In oneembodiment, the mammal is a human.

An aspect of the invention relates to a method of treating diabetes in amammal, comprising the step of co-administering to a mammal in needthereof a therapeutically effective amount of a compound of the presentinvention or a pharmaceutically acceptable salt thereof; niacin; and aglitazone selected from the group consisting of troglitazone,rosiglitazone, and pioglitazone. In one embodiment, the co-administeringis co-administering orally. In one embodiment, the mammal is a human.

An aspect of the invention relates to a method of treating diabetes in amammal, comprising the step of co-administering to a mammal in needthereof a therapeutically effective amount of a pharmaceuticalcomposition of the present invention; niacin; and a glitazone selectedfrom the group consisting of troglitazone, rosiglitazone, andpioglitazone. In one embodiment, the co-administering isco-administering orally. In one embodiment, the mammal is a human.

An aspect of the invention relates to a method of treating diabetes in amammal, comprising the step of co-administering to a mammal in needthereof a therapeutically effective amount of a compound of the presentinvention or a pharmaceutically acceptable salt thereof; and a fibrateselected from the group consisting of fenofibrate and bezafibrate. Inone embodiment, the co-administering is co-administering orally. In oneembodiment, the mammal is a human.

An aspect of the invention relates to a method of treating diabetes in amammal, comprising the step of co-administering to a mammal in needthereof a therapeutically effective amount of a pharmaceuticalcomposition of the present invention; and a fibrate selected from thegroup consisting of fenofibrate and bezafibrate. In one embodiment, theco-administering is co-administering orally. In one embodiment, themammal is a human.

An aspect of the invention relates to a method of treating diabetes in amammal, comprising the step of co-administering to a mammal in needthereof a therapeutically effective amount of a compound of the presentinvention or a pharmaceutically acceptable salt thereof; niacin; and afibrate selected from the group consisting of fenofibrate andbezafibrate. In one embodiment, the co-administering is co-administeringorally. In one embodiment, the mammal is a human.

An aspect of the invention relates to a method of treating diabetes in amammal, comprising the step of co-administering to a mammal in needthereof a therapeutically effective amount of a pharmaceuticalcomposition of the present invention; niacin; and a fibrate selectedfrom the group consisting of fenofibrate and bezafibrate. In oneembodiment, the co-administering is co-administering orally. In oneembodiment, the mammal is a human.

In certain embodiments, the present invention relates to any one of theaforementioned methods and the attendant limitations, wherein saidmammal is a primate, bovine, ovine, rodent, equine, canine, or feline.

In certain embodiments, the present invention relates to any one of theaforementioned methods and the attendant limitations, wherein saidmammal is a human.

In certain embodiments, the present invention relates to any one of theaforementioned methods and the attendant limitations, wherein saidcompound, compounds, or pharmaceutical composition are administeredorally.

In certain embodiments, the present invention relates to any one of theaforementioned methods and the attendant limitations, wherein saidcompound, compounds, or pharmaceutical composition are administeredintravenously.

In certain embodiments, the present invention relates to any one of theaforementioned methods and the attendant limitations, wherein saidcompound, compounds, or pharmaceutical composition are administeredsublingually.

In certain embodiments, the present invention relates to any one of theaforementioned methods and the attendant limitations, wherein saidcompound, compounds, or pharmaceutical composition are administered byinhalation.

In certain embodiments, the present invention relates to any one of theaforementioned methods and the attendant limitations, wherein saidcompound, compounds, or pharmaceutical composition are administeredocularly.

In certain embodiments, the present invention relates to any one of theaforementioned methods and the attendant limitations, wherein saidcompound, compounds, or pharmaceutical composition are administeredtransdermally.

In certain embodiments, the present invention relates to any one of theaforementioned methods and the attendant limitations, wherein saidcompound, compounds, or pharmaceutical composition are administeredrectally.

In certain embodiments, the present invention relates to any one of theaforementioned methods and the attendant limitations, wherein saidcompound, compounds, or pharmaceutical composition are administeredvaginally.

In certain embodiments, the present invention relates to any one of theaforementioned methods and the attendant limitations, wherein saidcompound, compounds, or pharmaceutical composition are administeredtopically.

In certain embodiments, the present invention relates to any one of theaforementioned methods and the attendant limitations, wherein saidcompound, compounds, or pharmaceutical composition are administeredintramuscularly.

In certain embodiments, the present invention relates to any one of theaforementioned methods and the attendant limitations, wherein saidcompound, compounds, or pharmaceutical composition are administeredsubcutaneously.

In certain embodiments, the present invention relates to any one of theaforementioned methods and the attendant limitations, wherein saidcompound, compounds, or pharmaceutical composition are administeredbuccally.

In certain embodiments, the present invention relates to any one of theaforementioned methods and the attendant limitations, wherein saidcompound, compounds, or pharmaceutical composition are administerednasally.

EXEMPLIFICATION

The invention now being generally described, it will be more readilyunderstood by reference to the following, which is included merely forpurposes of illustration of certain aspects and embodiments of thepresent invention, and is not intended to limit the invention.

Example 1 Synthetic Schemes A. Compound ARI-001

Reaction conditions: i. HCHO, Morpholine.HCl, n-PrOH, 100° C.; ii. NaOH,then HCl.

6-methyl-nicotinic acid methyl ester (4.5 g, 30 mmol), morpholinehydrochloride (1.85 g, 15 mmol), n-PrOH (18 mL) and formaldehydesolution (in water, 37%) (1.2 g, 15 mmol) were added to a 50 mL flaskequipped with a condenser. The reaction mixture was refluxing with apre-heated 100° C. oil bath for 2.5 hr under argon. Then the mixture wasallowed to stand at room temperature overnight and a yellow needlecrystal was precipitated out (If there was no precipitation formed atroom temperature, cold room (4° C.) or even −10° C. fridge would berecommended). Isolated the crystal by filtration and washed with alittle ethyl ether to afford the crude product of step 1 as a HCl salt(1.5 g, 35% yield; purity was about 95%, the double Mannich additionby-product was about 3%). This crude product was further purified by onetime re-crystallized from n-PrOH and MeOH to give the purer product ofstep 1 as an off-white or pale yellow powder (1.2 g, 28% yield; puritywas 99.1%, the double Mannich addition by-product was 0.9%).

The product of step 1 (1.5 g, 5 mmol) was dissolved in MeOH (20 mL) andwater (10 mL), 1 N LiOH (15 mL) was added under ice-water cooling. Theresulting mixture was stirred at room temperature overnight, and thenadjusted pH to 2-3 with 2N HCl. After condensed under vacuum the residuewas then further purified with preparative HPLC eluting with solventacetonitrile and water (5 mM HCl added) to afford 1.2 g of the targetcompound ARI-001 as a white powder (HCl salt, total yield was about 30%for two steps when used the crude product of step 1).

B. Compound ARI-002

Reaction conditions: i. HCHO, Morpholine.HCl

C. Compound ARI-001D

Reaction conditions: i. HCHO, Morpholine-d8.HCl; ii. NaOH, then HCl.

D. Compound ARI-005

Reaction conditions: i. 5-Indanol, EDAC, DMAP.

E. Compound ARI-006 (Hexa ARI-001 Inositol)

Reaction conditions: i. imyo-Inositol, EDCI, DMAP.

F. Compound ARI-008

Reaction conditions: i. D-Sorbitol, EDAC, DMAP.

G. Compound ARI-010

Reaction conditions: i. ARI-001, EDAC, DMAP; ii. Bu₄NI, BCl₃.

Example 2 In Vitro Studies

ARI-001 was synthesized as described above. Purity was determinedindependently before use in experiments by examination via liquidchromatography-mass spectroscopy (LC-MS). A sample of material wasdissolved in water/acetonitrile and injected onto a Discovery C-18reverse phase column. The mobile phase began as 2%:98%acetonitrile:water, which was held for three minutes, after which alinear gradient was started that ran over 6 minutes, increasing thepercent of acetonitrile until a final ratio of 98%:2% acetonitrile:waterwas reached. This final ratio was held for 3 minutes. UV detection wascollected at 215 nm, as shown in FIG. 1. The major peak was identifiedas ARI-001.

The purity was determined by the ratio of the area of the major peak(3.59 minutes) to the sum of areas of all peaks. Purity was determinedto be 98.9%. The minor peaks were not identified.

Stability was determined by storing ARI-001 under 50° C. with nospecified humidity requirement. At various time points over the courseof 3 months (90 days), a small sample (<5 mg) of ARI-001 was collectedfor analysis using LC-MS under the same conditions as used for puritydetermination (vide supra). FIG. 2 shows the time course of stability ofARI-001 under such conditions.

Under standard conditions (50° C., unregulated humidity), ARI-001remained 98.9% pure for a period of 65 days. Only by 90 days at 50° C.did ARI-001 begin to show any degradation. After 90 days, the compoundwas found to be 95.9% pure.

Example 3 In Vivo Studies

To investigate the effects of ARI-001 on lipid modulation, a hamstermodel was developed and utilized in the setting of chronicadministration of compound. This model, its development, and the effectsof ARI-001 are described herein.

Effects of Diet Modification on the Lipid Profile of Hamsters.

Like other rodents, the lipid profile in Golden Syrian hamsterspredominantly consists of HDL, with little LDL or VLDL cholesterol.However, on a high-fat diet, hamsters experience an increase in thecholesterol pool, including triglycerides and free fatty acids. Adding asugar to the drinking water source such as 10% fructose expands thetriglyceride pool significantly, including the VLDL. On this diet, thehamster becomes a useful model for investigating the role of modulatorson triglycerides and VLDL, and LDL cholesterol. Indeed, literaturesources have utilized this model to investigate triglyceride and freefatty acid modulating compounds such as fenofibrate.

We examined the effects of diet modulation on the lipid profile of maleSyrian Golden hamsters. Hamsters were ordered from Charles River Labs(Wilmington, Mass.), and requested to be 111-120 g in weight(correspondingly 56-61 days old). Hamsters were kept in cages of 4-5 percage, and maintained on a standard light cycle of 12 hours on/12 hoursoff. All diets were obtained from Dyets, Inc. (Bethlehem, Pa.). “NormalDiet” was a standard rodent chow, catalog #5001, produced into pellets.Water and this standard chow diet were available to this group ofhamsters ad libitum. Food was added to cages as needed, but no lessfrequently than twice per week. “High Fat Diet” was the same standardrodent chow supplemented with the following: 11.5% corn oil, 11.5%coconut oil, 0.5% cholesterol, and 0.25% deoxycholate. This is alsoavailable directly from Dyets, Inc., as catalog #611201. Both diets wereordered in 10 kg batches and stored at 4° C. for durations of theexperiments (4-8 weeks), and at −20° C. for longer storage (up to sixmonths). Water and this high fat diet were available to this group ofhamsters ad libitum. The “High Fat+Fructose” group was fed the samefat-supplemented chow as the “high fat diet” group (#611201), but waterwas supplemented with fructose to a final concentration of 10%. Fructosewas supplied from Now Foods (catalog #6931) and distributed by LuckyVitamin (catalog #WB48432). Fructose water was prepared by adding 400 gof fructose to 4 L of water and stirring at room temperature untildissolved. Fructose water was stored at 4° C. until use. When providedto hamsters, fructose water was kept in a water bottle in the hamstercages at room temperature, exactly as standard water was. Fructose waterand high fat chow were provided to this group of hamsters ad libitum.All animals remained on their respective diets for 21 days.

To begin this experiment, hamsters were randomly assigned to groupsdefined by the diet modifications above. After a fixed time, blood wascollected from hamsters (N=3-4) to determine the lipid contents of theplasma. Because of limitations in the ability to adequately collectblood from hamsters, all blood samples were obtained via a terminalcardiac puncture preceded by asphyxiation with carbon dioxide. Blood(approximately 2 mL volume) was collected with a 22 G needle into a 5 mLsyringe and transferred to a K₂EDTA tube. The samples were kept on iceuntil centrifugation (14,000 rpm for 10 minutes at 4° C.) to separateplasma. Plasma was then aliquoted to tubes for storage at −80° C. untilanalysis.

Lipid parameters were determined using commercially available kits fromWako USA (Richmond, Va.) according to manufacturer's directions.

TABLE 1 Lipid values from hamsters on one of three different diets for21 days. Hamsters were sacrificed and their plasma was analyzed asdescribed. Values represent the average of measurements of eachparameter (N = 3), with standard deviation. TC: total cholesterol; HDL:high-density lipoprotein cholesterol; LDL: low-density lipoproteincholesterol; TG: triglycerides; FFA: free fatty acids. TC (±SD) HDL(±SD) LDL (±SD) TG (±SD) FFA (±SD) Day 21 (mg/dL) (mg/dL) (mg/dL)(mg/dL) (mEq/L) Normal Diet 115 ± 8   63 ± 6 17 ± 3  325 ± 89  0.76 ±0.02  High Fat Diet 680 ± 82*** 130 ± 16  384 ± 20*** 1129 ± 123** 1.65± 0.42*  High Fat + 654 ± 135**  97 ± 41 282 ± 85** 1658 ± 673*  2.17 ±0.43** Fructose *p < 0.05 compared to Normal Diet within the sameparameter **p < 0.01 compared to Normal Diet within the same parameter***p < 0.001 compared to Normal Diet within the same parameter

Lipid values from control animals (zero days on any of the three dietsdescribed above) were essentially indistinguishable (see Table 1). Byday 21, both diet modifications had significant effects on the lipidprofiles of these hamsters when compared to animals on normal chow diet.All parameters were significantly increased from control (p<0.05 in allgroups), with the exception of HDL. As predicted, the addition offructose to the high fat diet further increased the triglyceride andfree fatty acid concentrations to a greater extent than the high fatdiet alone. HDL was unchanged from the normal diet group, regardless ofthe diet modification.

Fast protein liquid chromatography (FPLC) was used to separate thedifferent cholesterol subpopulations from samples of hamster plasma.Briefly, plasma from each animal within a given cohort was pooledtogether and applied to an AKTA liquid handling system with a Superose 610/300 GL column (product #14-5172-01, GE Life Sciences). 250 μL ofsample was applied to the injection system, diluted with 5 mL of buffer(100 mM Na₂HPO₄, 100 mM NaCl, pH 7.5), loaded onto the column, andeluted with 23.5 mL of buffer at a flow rate of 1.0 mL/min, intofractions of size 0.24 mL. Each fraction was individually measured forcholesterol concentration using the total cholesterol kit from Wako asdescribed above with the following modification: sample volume wasincreased to 30 μL and the reagent volume was decreased to 60 μL.

FPLC traces produce continuous curves with three distinct peaks,representing each of the cholesterol subpopultions: VLDL, LDL, and HDL.Because the column used in this experiment is a size-exclusion column,the largest particles appear first, while the smallest appear last.Hence, VLDL is the first peak on the trace, followed by LDL, with HDLappearing last. If each of these peaks is assumed to take a Gaussiandistribution, one can deconvolute the FPLC trace into each of thesethree components to determine the contribution that each component makesto the whole curve.

FIG. 3 illustrates the FPLC traces of plasma pooled from hamsters on twodifferent diets for three weeks. The VLDL curve is vastly expanded onthe high fat+fructose diet. The LDL peak is also much higher.Interestingly, there is very little difference in the HDL peak,indicating that the diet modification has a much more powerful effect onthe non-HDL cholesterol population. This model then lends itself tobeing a useful means by which to measure the effects of ARI-001 on VLDLand LDL cholesterol.

ARI-001 Lowers LDL Cholesterol, Triglycerides, and Free Fatty AcidLevels in HF/HS Hamsters.

Male Golden Syrian hamsters were purchased from Charles River Labs(111-120 g, 56-61 days) and acclimated to a high fat+fructose (herein,referred to as “HF/HS”) diet as described above for two weeks. Hamsterswere assigned into cohorts by body weight after two weeks' acclimationto the diet. Twelve hamsters were assigned to the vehicle group, 9 wereassigned to receive niacin at a dose of 1200 mg/kg, 10 were assigned toreceive ARI-001 at a dose of 1120 mg/kg, and 10 were assigned to receiveARI-001 at a dose of 2240 mg/kg. At the end of this diet acclimationperiod, hamsters were orally gavaged with 1 mL of a solution of vehicle(water), niacin, or ARI-001 at one of the two doses. Hamsters were dosedonce per day for a total of 18 days. All animals remained on theabove-described HF/HS diet throughout the dosing period. Dosingsolutions for each cohort were prepared for 7 days at a time, althoughenough was prepared to last for 8 days. Each solution was stored at roomtemperature between administrations. Cohorts were defined according toTable 2 below. Because of the molecular weight difference between niacinand ARI-001, doses are given in both mg/kg and mmol/kg. Note that 1200mg/kg of niacin is equivalent to 2240 mg/kg of ARI-001 on a molar basis.

TABLE 2 Assignments to cohorts for 18 day dosing study in HF/HShamsters. Dose Dose Compound (mg/kg) (mmol/kg) Animals Days Vehicle 0 012 18 Niacin 1200 9.75 10 18 ARI-001 1120 4.88 10 18 ARI-001 2240 9.7510 18

As shown in Table 3, ARI-001 given via oral gavage for 18 days at 2240mg/kg lowered the LDL-cholesterol and total cholesterol levels in aHF/HS hamster model. ARI-001 also lowered triglycerides and free fattyacid levels, with very little variation between animals as illustratedby the small standard deviation. At the molar equivalent dose of 1200mg/kg, niacin was unable to confer these effects in this animal model,suggesting that ARI-001 is at least 1.67-times more efficacious thanniacin with respect to the LDL cholesterol parameter, and at least1.54-times more efficacious than niacin with respect to the totalcholesterol parameter. Of note are the triglyceride and free fatty acidvalues, which demonstrated responders among all animals in the 2240mg/kg ARI-001 group. That there is a very small standard deviation amongthese data points reflects the impressive response rate among theseanimals. The HDL/TC ratio was calculated by dividing each individualhamster's HDL cholesterol level by his total cholesterol level. Thefraction that resulted is the HDL/TC ratio. This parameter was higherthan the vehicle cohort's, with impressive statistical significance(p<0.001). This does not likely represent a powerful increase in HDL, asthe absolute HDL value measured was increased by only 33% in the 2240mg/kg ARI-001 group compared to vehicle. Rather, the very powerfulchange in the HDL/TC ratio likely represents a system-wide reduction incholesterol populations, with the exception of HDL, which was not onlyspared from such reductions, but was possibly increased.

TABLE 3 Lipid parameters from HF/HS hamsters dosed orally with vehicle,niacin, or ARI- 001 for 18 days. TC, total cholesterol. Values given aremean ± standard deviation. P- values are reported from 2-tailed unpairedt-tests comparing to vehicle treated within the same parameter. TC HDLLDL TG FFA (mg/dL) (mg/dL) (mg/dL) (mg/dL) (mEq/L) HDL/TC Cohort ±SD ±SD±SD ±SD ±SD ±SD Vehicle 857 ± 422 139 ± 32 253 ± 82 1065 ± 465 1.95 ±0.53 0.21 ± 0.11 Niacin: 552* ± 183    79 ± 26***  170 ± 52* 1555 ± 8081.82 ± 0.69 0.17 ± 0.11 1200 mg/kg ARI-001: 653 ± 194 142 ± 34 253 ± 91 957 ± 550  1.39 ± 0.65* 0.24 ± 0.14 1120 mg/kg ARI-001:  343 ± 104** 186 ± 74*   114 ± 33***   138 ± 80***   0.75 ± 0.15***   0.48 ± 0.07***2240 mg/kg *p < 0.05 compared to Vehicle within the same parameter **p <0.01 compared to Vehicle within the same parameter ***p < 0.001 comparedto Vehicle within the same parameter

The measured HDL values were borderline significant (p=0.06) between the2240 mg/kg ART-001 group and vehicle. There was a considerable increasein significance when considering the calculated HDL/TC values. The FPLCtraces also demonstrated a significant difference in lipid profilebetween these two groups. FPLC was performed as described above. Curveswere deconvoluted as described above. Not only were the VLDL and the LDLpeaks considerably decreased compared to vehicle, but the HDL curve wasnotably larger in the ART-001 trace. See FIG. 4.

Male Golden Syrian hamsters from the previously described experimentdemonstrated a dose dependence on ART-001 with respect to lipidalteration. 2240 mg/kg is an effective dose for 18 days of dailytreatment for nearly all parameters: total cholesterol, LDL cholesterol,triglycerides, and free fatty acids. However, 1120 mg/kg shows onlymodest effects on these parameters, with only the free fatty acidsparameter demonstrating a statistically significant effect compared tovehicle. Nonetheless, the trend is clear between the doses for all lipidparameters investigated, as shown in FIG. 5. Moreover, at the molarequivalent dose, ARI-001 effects a more powerful response than niacin inall lipid parameters measured.

ARI-001 Lowers LDL Cholesterol, Triglycerides, and Free Fatty Acids in aTime-Dependent Manner.

Thirty-two male Golden Syrian hamsters were acclimated over two weeks toa HF/HS diet as described above. After a two week induction period,animals were assigned to cohorts for 18 days of study on either vehicleor ARI-001 (1120 mg/kg), or to cohorts for 28 days of study on eithervehicle or ARI-001 (1120 mg/kg). Each of the four groups had 8 hamsters.Solutions were prepared and stored as described above Animals were doseda volume of 1 mL per day for either 18 or 28 consecutive days, aspreviously described. At the end of the study, hamsters were sacrificed,their blood collected into K₂EDTA tubes, plasma separated bycentrifugation and frozen until analysis. All lipids were analyzed usingcommercially available kits (Wako USA) as described above. In Table 4below, both 18-day and 28-day vehicle animals are combined into a singlevehicle group (N=16).

TABLE 4 Lipid parameters from HF/HS hamsters dosed orally with vehicleor ARI-001 for 18 days or 28 days. Values given are mean ± standarddeviation. P-values are reported from 2-tailed unpaired t-testscomparing to vehicle treated within the same parameter. TC HDL LDL TGFFA (mg/dL) (mg/dL) (mg/dL) (mg/dL) (mEq/L) HDL/TC Cohort ±SD ±SD ±SD±SD ±SD ±SD Vehicle 796 ± 253 135 ± 40 363 ± 85  1023 ± 630  1.30 ± 0.450.19 ± 0.09 ARI-001: 668 ± 239 153 ± 30 346 ± 121 833 ± 410 1.06 ± 0.560.27 ± 0.15 1120 mg/kg, 18 Days ARI-001:  420 ± 85*** 138 ± 26  175 ±80***  388 ± 82**   0.56 ± 0.12***   0.34 ± 0.09*** 1120 mg/kg, 28 Days**p < 0.01 compared to Vehicle within the same parameter ***p < 0.001compared to Vehicle within the same parameter

ARI-001 showed favorable effects on lipids when a dose of 1120 mg/kg wascarried out to 28 days. When hamsters were dosed for 28 days instead of18 days, all lipid parameters measured achieved a statisticallysignificant difference compared to vehicle, except for HDL, which showedno difference compared to vehicle. The reductions seen at 1120 mg/kg for28 days were greater than after 18 days of dosing. However, thesereductions were not nearly as impressive as those seen with 18 days atthe higher dose of 2240 mg/kg.

Correlation Between Plasma Lipid Biomarkers and ARI-001 PlasmaConcentrations.

Plasma from the 19 hamsters dosed with ARI-001 in the above described18-day study was analyzed for concentrations of ARI-001. Concentrationswere determined for these samples, which were collected 24 hours afterthe final dose was administered. Briefly, plasma drug concentrations forthe non-GLP pharmacokinetic experiments were determined by LC-MS usingan Applied Biosystems 4000Qtrap spectrometer with electrosprayionization. Samples were prepared for analysis by precipitation ofplasma proteins with cold methanol. HPLC of the samples was done with anAgilent Eclipse C18 column and a methanol/water gradient containing 0.1%formic acid and 5 mM ammonium acetate. ARI-001 was detected usingmultiple reaction monitoring (MRM) in the positive ion mode. Forquantitation, a standard curve was measured by addition of known amountsof ARI-001 to plasma from untreated animals and preparing in a manneridentical to the samples from treated animals. All plasma samples werespiked with 10 ng/mL of isotope-enriched ARI-001 which served as aninternal standard for the LC-MS measurements. All compoundconcentrations are reported in μM. For correlation analysis, plasmaconcentrations of ARI-001 in a given animal were paired with that sameanimal's lipid parameter. All animals from both dosing groups (1120mg/kg and 2240 mg/kg) were included in the analysis. These correlationsare graphed in FIG. 6 and FIG. 7. Pearson r values were determined usingall data points, as was the two-tailed P-value for the data set.

Lipid parameter changes correlated well with plasma levels of drugmeasured 24 hours after the final dose. Indeed, total cholesterol, HDLcholesterol, LDL cholesterol, triglycerides, and free fatty acid levelsall achieved statistically significant levels of correlation (p<0.01).Correlation with triglycerides were especially notable for having a veryhigh degree of statistical significance, p<0.001. These significantcorrelations give support to the idea that ARI-001 is directlyresponsible for modulation in lipid values. Moreover, these datacorroborate the dose-response effects seen in FIG. 5.

ARI-001 Concentrations in Tissues Correlate with Plasma Lipid Levels.

Tissue samples were harvested from hamsters in the above-described18-day experiment to determine the concentrations of ARI-001 in bothliver and adipose tissue. Briefly, liver and adipose samples wereharvested at the termination of the experiment; the samples were flashfrozen in liquid nitrogen and then stored at −80° C. until used foranalysis. To prepare for analysis, a sample of liver was excised fromthe frozen mass, weighed, and homogenized with a tissue grinder followedby sonication in buffer. The solid materials were then removed bycentrifugation. To prepare for LC-MS analysis, the homogenate was thentreated to the same preparation technique described for plasmapreparation (vide supra). A sample of adipose was excised from thefrozen mass, and transferred to a mortar and pestle cooled with liquidnitrogen. During grinding, liquid nitrogen was added to ensure thesample of adipose remained solid. The ground sample was transferred to atared tube to weigh total sample. This ground sample was extracted withmethanol, and this compound-containing methanol was separated from lipidby cooling to −20° C. After drying, the methanol sample was dissolved inwater; the samples were then prepared for LC-MS analysis in the same waythat liver and plasma were (vida supra).

Liver concentrations were reported as ng of ARI-001 per mL ofhomogenized tissue sample extracted into buffer. Concentrations inadipose were reported as ng of ARI-001 per mg of tissue recovered fromthe grinding process. Because of the distribution of tissueconcentrations and lipid parameters, the logarithm transformation wasused on all liver samples when determining correlation. Additionally,adipose concentrations were transformed as logarithm +1, since thelogarithm transformation produced negative values for these tissuesamples. These transformations allowed the data to be more graphed moreconveniently. Finally, these transformations are valid because thenature of the Pearson r correlation coefficient is invariant to bothlogarithm transformation and to transposition.

FIG. 8 graphs the correlation between concentrations of ARI-001 inplasma versus liver (left), and in plasma versus adipose (right). Bothof these correlations were highly statistically significant, with p<0.01for each pair of parameters. FIGS. 9-11 graph the correlations betweenthe concentrations of ARI-001 in each tissue sample versus the lipidparameters TC, HDL, LDL, TG, and FFA. All concentration measurements andall lipid parameters were transformed via logarithm. Pearson r wasdetermined using all data points illustrated. P-value was determined fora 2-tailed t-test using all data points illustrated.

ARI-001 Increases ABCA1, ApoAI, SR-BI, CETP, and Adiponectin mRNA inHF/HS Hamsters.

Investigation of a possible mechanism that could lead to the increase inHDL cholesterol focused on changes in the mRNA levels of several genesrelated to the regulation of HDL. Hamster livers and adipose werepreared in manners similar to that described for ARI-001 concentrationdetermination. Briefly, to prepare for analysis, a sample of liver wasexcised from the frozen mass, weighed, and homogenized with a tissuegrinder followed by sonication in buffer. The solid materials were thenremoved by centrifugation. The resulting lysate was used in qPCRanalysis to quantify the specific mRNA measured (vide infra) usingprimers designed for the specific sequences of interest. All mRNAquantities were normalized to vehicle-treated animal, and mRNA levelswere expressed as a fold increase or decrease relative tovehicle-treated. The adipose was treated in a similar manner to theliver: a sample of adipose was excised from the frozen mass, andtransferred to a mortar and pestle cooled with liquid nitrogen. Duringgrinding, liquid nitrogen was added to ensure the sample of adiposeremained solid. The ground sample was transferred to a tared tube toweigh total sample. This ground sample was treated with buffer andprepared for qPCR to quantify specific mRNA quantities.

TABLE 5 Relative concentrations of ABCA1, ApoAI, SR-BI, CETP mRNA per mgof liver tissue, and likewise adipose CETP and adiponectin mRNA per mgof adipose tissue, from high fat-fed hamsters in vehicle-, niacin-, orARI-001-treated cohorts. Values are given as a fold- change compared tothe mean of the vehicle values. Niacin: ARI-001: Message Vehicle 1200mg/kg 2240 mg/kg Liver ABCA1 1.02 ± 0.18 0.80 ± 0.18 1.54 ± 0.48** Liver ApoAI 1.04 ± 0.28 1.17 ± 0.19 1.72 ± 0.24*** Liver SR-BI 1.00 ±0.25 0.79 ± 0.18 1.50 ± 0.33**  Liver CETP 1.00 ± 0.45 1.03 ± 0.55 2.05± 0.38*** Adipose CETP 1.00 ± 0.46 1.12 ± 0.33 1.72 ± 0.70*  Adipose1.00 ± 0.43   1.67 ± 0.32*** 2.00 ± 0.23*** Adiponectin

Both ABCA1 and ApoAI mRNA levels were higher in the ARI-001-treated armsrelative to vehicle control animals. Indeed, a statistically significantcorrelation was seen between HDL and ApoAI mRNA levels. This suggests apossible mechanism by which ART-001 may increase HDL in this hamstermodel.

TABLE 6 Correlations between ABCA1, ApoAI, SR-BI, and CETP mRNA per mgof liver tissue vs HDL levels, and likewise between CETP and adiponectinmRNA per mg of adipose tissue vs HDL levels, from high fat-fed hamstersin vehicle-, niacin-, or ARI-001-treated cohorts. Correlation VehicleNiacin: 1200 mg/kg ARI-001: 2240 mg/kg [HDL] vs Liver ABCA1 −0.007(−0.60 . . . 0.60)  −0.40 (−0.84 . . . 0.36)  0.49 (−0.33 . . . 0.89)[HDL] vs Liver ApoAI 0.32 (−0.34 . . . 0.77) 0.19 (−0.54 . . . 0.76)0.80 (0.21 . . . 0.96)* [HDL] vs Liver SR-BI 0.46 (−0.19 . . . 0.83)0.46 (−0.29 . . . 0.86) −0.10 (−0.75 . . . 0.65)  [HDL] vs Liver CETP0.18 (−0.47 . . . 0.70) −0.13 (−0.73 . . . 0.58)  0.30 (−0.52 . . .0.83) [HDL] vs Adipose CETP −0.03 (−0.62 . . . 0.58)  0.54 (−0.19 . . .0.89) 0.85 (0.28 . . . 0.98)* [HDL] vs Adipose 0.43 (−0.22 . . . 0.82)0.31 (−0.48 . . . 0.81) −0.22 (−0.83 . . . 0.64)  Adiponectin

Example 4 Safety Pharmacology Studies (Non-GLP Preliminary Studies)

Because niacin is known to be associated with liver toxicity and glucoseintolerance in a chronic dosing setting, we examined whether ARI-001, aniacin mimetic, could be associated with similar issues. In order toinvestigate this, we examined the common liver functional enzymes ASTand ALT in the plasma of hamsters from experiment described above inExample 3. These animals were dosed for 18 consecutive days, while beingon a HF/HS diet for a total of nearly 5 weeks. We also examined theglucose levels in the plasma of these animals. For pharmacokineticstudies, we utilized wild type mice for both single and repeatedadministration study. Finally, pharmacokinetic studies were corroboratedby data from single and repeated administration to monkeys.

A. Effects on Liver Function

ARI-001 Improves Liver Function Tests from Chronically Dosed HighFat-Fed Hamsters.

Certain formulations of niacin are known to cause hepatotoxicity inhumans. This led to an investigation of liver function tests (AST, ALT)from plasma of hamsters dosed for 18 days with ARI-001. AST and ALT weremeasured using commercially available kits (Bio-Quant Diagnostic Kits,San Diego, Calif.). As expected, AST and ALT values from untreatedhamsters (vehicle group) were very high, as the high fat diet leads tohepatomegaly and fatty liver. This disease state is reflected in theelevated AST and ALT levels. In contrast, AST and ALT levels fromARI-001 treated animals were significantly lower than vehicle. Indeed,AST was drastically reduced at the 2240 mg/kg dose, and evensignificantly reduced at the 1120 mg/kg dose. ALT values were similarlyreduced, again in a dose-dependent manner. See FIG. 12A and FIG. 12B.

B. Effects on Glucose Tolerance

ARI-001 Has No Effect on Glucose Levels among High Fat-Fed Hamsters.Niacin is known to adversely affect glucose levels among diabeticpatients. The hamster model used in this experiment did produce apopulation with elevated glucose levels, as demonstrated by the vehiclegroup in FIG. 13. Consistent with effects seen in humans, the glucose ofniacin-treated animals was increased relative to vehicle. However,neither dose of ARI-001 produced any significant change in glucoselevels in comparison to the vehicle cohort.

Example 5 Pharmacokinetic Studies A. Mouse In Vivo Studies

Single-Dose Pharmacokinetic Study of ARI-001 in Wild Type Mice.

Wild type C57BL/6 mice were dosed with a single administration ofARI-001 in solution either via oral gavage (PO) or via intraperitonealinjection (IP). Blood samples were then collected at various time pointsover a 24-hour period; plasma was then analyzed for concentrations ofARI-001 as described earlier. ARI-001 was administered at either a doseof 2240 mg/kg as a single bolus via oral gavage, or a dose of 448 mg/kgas a single bolus via intraperitoneal injection. See FIG. 14.

Single-dose administration of ARI-001 via oral gavage andintraperitoneal injection produced pharmacokinetic curves withparameters described in Table 7. By the 24 hour timepoint, the remainingconcentration of ARI-001 was undetectable.

TABLE 7 Pharmacokinetic parameters from single administration of ARI-001in wild type mice. ARI-001 C_(max) (μM) t_(1/2) (h) t_(max) (h) AUC(μM*h) PO 289 1.5 0.5 1096 IP 450 0.5 0.25 439

Multiple Administration Pharmacokinetic Study of ARI-001 in Wild TypeMice.

Wild type C57BL/6 mice were dosed with ARI-001 in solution via oralgavage daily for 30 consecutive days. Over the course of five 24-hourperiods, blood was collected, and the resultant plasma was analyzed forconcentrations of ARI-001. Four doses were used: 996 mg/kg, 1493 mg/kg,2240 mg/kg, and 3360 mg/kg. As expected, C_(max) levels and total24-hour exposure (AUC) were dose-dependent. However, these values weretime-independent, as there was no trend observed between theseparameters and days of administration. See FIGS. 15A-15D and FIGS.16A-16B.

B. Further Mouse In Vivo Studies

Single-Dose Pharmacokinetic Study in Wild Type Mice.

Wild type C57BL/6 mice were dosed with a single administration ofniacin, ARI-001, or compound 2230C (disclosed in US Patent ApplicationPub. No. 2009/0312355 A1, incorporated herein by reference) in solutionvia single bolus oral gavage (PO). Compound 2230C has the structure

Blood samples were then collected at various time points over a 24-hourperiod; plasma was then analyzed for concentrations of niacin, ART-001,and 2230C as described earlier. Results are shown in Table 8.

TABLE 8 Comparison of pharmacokinetic parameters of niacin, ARI-001, and2230C from single oral administration in wild type mice. Niacin ARI-0012230C C_(max) (μM) 4,089 309 126 AUC (μM h) 11,696 1,097 686 half-life(t_(1/2)) (h) 1.75 1.43 3.47 t_(max) (h) 0.50 0.38 0.31 C_(max) (%Niacin) 100 7.5 3.0 AUC (% Niacin) 100 9.4 5.8 C_(max)/AUC₀₋₂₄ (h⁻¹)0.35 0.28 0.18 C_(24 h)/C_(max) (%) 0.02 n.d. 2.1 n.d., not done

C. Golden Syrian Hamster In Vivo Studies

Single-Dose Pharmacokinetic Study of ARI-001 in Golden Syrian Hamsters.

The pharmacokinetic profile of ARI-001 was evaluated in HF/HS GoldenSyrian hamsters given aa single oral dose of 5.9 mmol/kg of ARI-001.Plasma samples were collected via cardiac puncture from five animals ateach time point to measure plasma concentrations of ARI-001 over 24hours. Results are shown in FIG. 17.

D. Monkey In Vivo Studies

Single-Dose Pharmacokinetic Study of ARI-001 in Macaque Monkeys.

Fasted monkeys were given a single administration of ARI-001 in solutioneither via oral gavage (PO) or via intravenous injection (IV). Bloodsamples were collected at various time points over a 24-hour period;plasma was then analyzed for concentrations of ARI-001. ART-001 wasadministered at either a dose of 288 mg/kg as a single bolus via oralgavage, or a dose of 96 mg/kg as a single bolus via IV injection.Results are shown in FIG. 18.

Single-Dose Pharmacokinetic Study of ARI-001 in Fed or Fasted Monkeys.

Fed monkeys were fed and allowed some time to digest before beingadministered ART-001 as a solution via oral gavage as previouslydescribed. Results are shown in FIG. 19.

Pharmacokinetics of Multiple Administrations of ARI-001 to FastedMonkeys.

ARI-001 was administered to monkeys via oral gavage once per day for atotal of seven days. Blood samples were collected after the first andafter the last administrations to measure plasma concentrations ofARI-001. There was very little difference between the plasmaconcentrations on day 1 versus day 7. The greatest point of discrepancywas in the C_(max) value, which was higher on day 7 than on day 1. Theconcentrations 24 hours after either the first or the last doses wereessentially identical. See FIG. 20.

Example 6 ARI-001 Fails to Recruit β-Arrestin to the Cell Membrane ofCells Expressing High Affinity Niacin Receptor GPR109A

It has been demonstrated that niacin-induced cutaneous flushing ismediated by activation of the niacin receptor, GPR109A, in aβ-arrestin-dependent manner. Walters R W et al. (2009) J Clin Invest119:1312-21. Assay-ready PathHunter eXpress β-Arrestin cells expressingGPR109A were plated at 10,000 cells/well in a 96-well plate andstimulated with either niacin or ART-001, each over a range ofconcentrations, for 90 minutes. G protein-coupled receptor (GPCR)activity was detected by measuring the interaction of β-arrestin withthe activated GPCR using 3-galactosidase enzyme fragmentcomplementation. Following stimulation with either niacin or ARI-001,signal was detected using the chemiluminescent PathHunter DetectionReagents. Representative results are shown in FIG. 21.

Unlike niacin, stimulation of GPR109A with ART-001 at concentrations upto 10 mM failed to recruit β-arrestin to the membrane of cellsexpressing GPR109A. Since niacin-induced flushing is known to bemediated by activation of GPR109A in a β-arrestin-dependent manner, thisfinding is consistent with the observation that ART-001 has greatlyreduced flushing side effect compared to niacin.

Example 7 Summary of Pharmacological Studies of ARI-001 in Animal Models

A number of pharmacokinetic, safety, and efficacy studies for ARI-001have been completed in a variety of animals, including mice, rats,Golden Syrian hamsters, dogs, and monkeys. Overall, results from thesestudies have established the following.

ARI-001 decreased plasma levels of total cholesterol, LDL-C, TG and FFAwhile increasing the absolute level of HDL-C and HDL-C/TC ratio. Thelipid altering effects of a once-daily dose of ARI-001 were morepronounced than the lipid effects observed with nearly 2-fold higherdose of niacin given once a day.

ARI-001 given once daily for 28 days produced a greater change in plasmalipid levels compared with the same dose of ARI-001 given once daily for18 days.

ARI-001 given once daily produced highly significant changes in plasmalipids, greater than or equal to the lipid altering effects observedwith the same total dose of ARI-001 given twice daily. Additionally,once daily ARI-001 was more potent than niacin in effecting desirablelipid changes.

Changes in plasma levels of TC, HDL-C, TG, LDL-C and FFA correlated withplasma concentrations of ARI-001 present in plasma

Plasma and liver concentrations of ARI-001 are proportionately related.

Liver concentration of ARI-001 correlated with decreases in plasma TC,LDL-C, TG and FFA and increases in plasma HDL-C.

ARI-001 showed no evidence of capillary vasodilation or hyperemia (aproxy of flush) in experiments using Doppler capillary blood flowmeasurements in mice. Additionally, clinical symptoms of “flushing” werenot observed over 28 days in rats or dogs.

Example 8 Human Clinical Trial with ARI-001

A randomized, double-blind, placebo-controlled study is performed withsequential escalating doses by cohort with observations for 30 hourspost dosing and return visit on 8th day. Study subjects are healthy maleand female adult volunteers, age 18-60 years, with LDL-C>130 mg/dL andweight <85 kg. Subjects are randomly assigned to receive study drug orplacebo.

Five periods of single dose escalation, with 8 subjects per cohort (6drug: 2 placebo) involve a total 40 subjects. Appropriately blindedmatching placebos are provided. Cohort 1 receives 500 mg of ARI-001formulated as a single oral tablet, plus eleven placebo tablets; Cohort2, 1000 mg taken as two 500 mg tablets of ARI-001, plus ten placebotablets; Cohort 3, 2000 mg taken as four 500 mg tablets of ARI-001, pluseight placebo tablets; Cohort 4, 4000 mg taken as eight 500 mg tabletsof ARI-001, plus four placebo tablets; Corhort 5, 6000 mg taken astwelve 500 mg tablets of ARI-001. Placebo-only subjects take twelveplacebo tablets. Each tablet is a compressed, film-coated tabletsuitable for oral administration.

Primary objectives of the study are to evaluate the safety andtolerability of single doses of ARI-001 in healthy adult volunteers, atdoses ranging from 500 mg to 6000 mg.

Secondary objectives of the study are to establish the pharmacokineticprofile of ARI-001 in blood after a single dose in healthy volunteers;observe changes in fasting triglycerides, free fatty acid and otherlipid biomarkers; correlate the dose level and plasma drug exposuresover time with any changes in fasting triglycerides, free fatty acid andother lipid biomarkers; and establish the effect of ARI-001 on symptomsof flushing by visual analog score (VAS).

Pharmacokinetic samples are collected at 0-45 min pre-dose and at 0.5,1, 1.5, 2, 4, 6, 8, 12, 24, 30 and 168 hours after dosing. The actualtime of each plasma collection is recorded.

At each collection, 3 mL of blood is collected into a Vacutainer tubecontaining EDTA (purple top) and refrigerated immediately. Within 30minutes of collection, the plasma fraction is separated bycentrifugation at 2,000 rpm for 15 minutes at 4° C. Analysis of allsamples is performed at a central laboratory.

On Day 1, pre-dose, the following procedures are performed:

-   -   Clinical laboratory tests including liver function (ALT, AST,        serum bilirubin), CK, hematology, APTT, PT, urinalysis and lipid        chemistry panel (LDL-C, HDL-C, free fatty acids, triglycerides,        LPA and ApoA-1)    -   12-lead ECG    -   Vital signs    -   VAS    -   Baseline plasma PK    -   Urine collection for baseline PK between midnight and 0 hours        (dosing)

After study drug administration, the following procedures are performed.

-   -   Clinical laboratory tests including liver function (ALT, AST,        serum bilirubin), CK, hematology and APTT, PT at 6, 12 and 24        hours post-dose    -   Lipid chemistry panel (LDL-C, HDL-C, free fatty acids,        triglycerides, Lp(a) and ApoA-1) at 4, 12 and 24 hours post-dose    -   12-lead ECG at 1, 2, 4, 6, 8, 12 and 24 hours post-dose    -   Urinalysis at 24 hours post-dose    -   Vital signs at 6, 12, 24 and 30 hours post-dose    -   VAS at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose    -   Physical examination at 24 hours post-dose and a brief clinical        examination at 30 hours post-dose    -   Collect blood sample for PK at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24        and 30 hours posts-dose    -   Collect blood sample for troponin at 4 hours post-dose    -   Collect urine for PK in 6 hour intervals at 0 to 6, 6 to 12, 12        to 18, 18 to 24, and 24 to 30 hours after dosing.

Preliminary results from this human clinical trial include theremarkable observation that no patients exhibited any signs of flushingat any dose of ARI-001, up to and including the 6000 mg dose.

Additional preliminary results are shown in FIG. 22, which illustratesdose response for triglyceride lowering in humans on single oral dosesof ARI-001 as measured 4 hours after dosing.

Further preliminary results are shown in FIG. 23, which illustratesserum concentration of ARI-001 as measured over 24 hours in humansfollowing single oral doses, ranging from 500 mg to 6000 mg, of ARI-001.C_(max) for the 2000 mg dose of ARI-001 was about 7500 ng/mL (7.5mg/mL); C_(max) for 1500 mg of niacin (roughly equimolar dose) was about30,000 ng/mL (30 mg/mL).

INCORPORATION BY REFERENCE

All publications and patents mentioned herein are hereby incorporated byreference in their entirety as if each individual publication or patentwas specifically and individually indicated to be incorporated byreference. In case of conflict, the present application, including anydefinitions herein, will control.

EQUIVALENTS

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. Manyvariations of the invention will become apparent to those skilled in theart upon review of this specification. The appended claims are notintended to claim all such embodiments and variations, and the fullscope of the invention should be determined by reference to the claims,along with their full scope of equivalents, and the specification, alongwith such variations.

1-45. (canceled)
 46. A method of treating a disease, disorder, orcondition selected from the group consisting of hyperlipidemia,hypercholesterolemia, lipodystrophy, dyslipidemia, atherosclerosis andcoronary artery disease, comprising the step of administering to amammal in need thereof a therapeutically effective amount of a compoundrepresented by structure I, or a pharmaceutically acceptable saltthereof:

wherein R is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, fused bicyclyl, carboxyalkyl, or arylalkenylaryl; R⁴ isselected independently for each occurrence from the group consisting ofdeuterium, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl,heteroaralkyl, halogen, nitro, cyano, sulfonic acid, alkylsulfoxyl,arylsulfoxyl, heteroarylsulfoxyl, aralkylsulfoxyl,heteroaralkylsulfoxyl, alkenylsulfoxyl, alkynylsulfoxyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio,heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl, formyloxy,acyloxy, formylthio, acylthio, amine, alkylamine, arylamine,heteroarylamine, aralkylamine, heteroaralkylamine, alkenylamine,alkynylamine, formylamine, acylamine, carboxyl, alkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl,heteroaralkyloxycarbonyl, amido, alkylaminecarbonyl, arylaminecarbonyl,heteroarylaminecarbonyl, aralkylaminecarbonyl, andheteroaralkylaminecarbonyl; R⁵ is independently for each occurrencehydrogen or lower alkyl; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and m is 1,2, 3, or
 4. 47. A method of treating a disease, disorder, or conditionselected from the group consisting of metabolic syndrome, obesity, fattyliver disease, and diabetes, comprising the step of administering to amammal in need thereof a therapeutically effective amount of a compoundrepresented by structure I, or a pharmaceutically acceptable saltthereof:

wherein R is hydrogen, alkyl, haloalkyl, alkenyl, alkenyl, carbocyclyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, fused bicyclyl, carboxyalkyl, or arylalkenylaryl; R⁴ isindependently for each occurrence selected from the group consisting ofdeuterium, alkyl, alkenyl, alkenyl, aryl, heteroaryl, aralkyl,heteroaralkyl, halogen, nitro, cyano, sulfonic acid, alkylsulfoxyl,arylsulfoxyl, heteroarylsulfoxyl, aralkylsulfoxyl,heteroaralkylsulfoxyl, alkenylsulfoxyl, alkynylsulfoxyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio,heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl, formyloxy,acyloxy, formylthio, acylthio, amine, alkylamine, arylamine,heteroarylamine, aralkylamine, heteroaralkylamine, alkenylamine,alkynylamine, formylamine, acylamine, carboxyl, alkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl,heteroaralkyloxycarbonyl, amido, alkylaminecarbonyl, arylaminecarbonyl,heteroarylaminecarbonyl, aralkylaminecarbonyl, andheteroaralkylaminecarbonyl; R⁵ is independently for each occurrencehydrogen or lower alkyl; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and m is 1,2, 3, or
 4. 48. A method of raising serum high-density lipoprotein (HDL)levels, comprising the step of: administering to a mammal in needthereof a therapeutically effective amount of a compound represented bystructure I, or a pharmaceutically acceptable salt thereof:

wherein R is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, fused bicyclyl, carboxyalkyl, or arylalkenylaryl; R⁴ isindependently for each occurrence selected from the group consisting ofdeuterium, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl,heteroaralkyl, halogen, nitro, cyano, sulfonic acid, alkylsulfoxyl,arylsulfoxyl, heteroarylsulfoxyl, aralkylsulfoxyl,heteroaralkylsulfoxyl, alkenylsulfoxyl, alkynylsulfoxyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio,heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl, formyloxy,acyloxy, formylthio, acylthio, amine, alkylamine, arylamine,heteroarylamine, aralkylamine, heteroaralkylamine, alkenylamine,alkynylamine, formylamine, acylamine, carboxyl, alkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl,heteroaralkyloxycarbonyl, amido, alkylaminecarbonyl, arylaminecarbonyl,heteroarylaminecarbonyl, aralkylaminecarbonyl, andheteroaralkylaminecarbonyl; R⁵ is independently for each occurrencehydrogen or lower alkyl; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and m is 1,2, 3, or
 4. 49. A method of lowering serum low-density lipoprotein (LDL)levels or lowering serum lipoprotein (a) levels, comprising the step ofadministering to a mammal in need thereof a therapeutically effectiveamount of a compound represented by structure I, or a pharmaceuticallyacceptable salt thereof:

wherein R is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, fused bicyclyl, carboxyalkyl, or arylalkenylaryl; R⁴ isindependently for each occurrence selected from the group consisting ofdeuterium, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl,heteroaralkyl, halogen, nitro, cyano, sulfonic acid, alkylsulfoxyl,arylsulfoxyl, heteroarylsulfoxyl, aralkylsulfoxyl,heteroaralkylsulfoxyl, alkenylsulfoxyl, alkynylsulfoxyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio,heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl, formyloxy,acyloxy, formylthio, acylthio, amine, alkylamine, arylamine,heteroarylamine, aralkylamine, heteroaralkylamine, alkenylamine,alkynylamine, formylamine, acylamine, carboxyl, alkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl,heteroaralkyloxycarbonyl, amido, alkylaminecarbonyl, arylaminecarbonyl,heteroarylaminecarbonyl, aralkylaminecarbonyl, andheteroaralkylaminecarbonyl; R⁵ is independently for each occurrencehydrogen or lower alkyl; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and m is 1,2, 3, or
 4. 50. A method of treating a disease, disorder, or conditionselected from the group consisting of congestive heart failure,cardiovascular disease, hypertension, coronary heart disease, angina,pellagra, Hartnup's syndrome, carcinoid syndrome, arterial occlusivedisease, hypothyroidism, vasoconstriction, osteoarthritis, rheumatoidarthritis, Alzheimer's disease, disorders of the peripheral and centralnervous system, hematological diseases, cancer, inflammation,respiratory diseases, and gastroenterological diseases, comprising thestep of administering to a mammal in need thereof a therapeuticallyeffective amount of a compound represented by structure I, or apharmaceutically acceptable salt thereof:

wherein R is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, fused bicyclyl, carboxyalkyl, or arylalkenylaryl; R⁴ isindependently for each occurrence selected from the group consisting ofdeuterium, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl,heteroaralkyl, halogen, nitro, cyano, sulfonic acid, alkylsulfoxyl,arylsulfoxyl, heteroarylsulfoxyl, aralkylsulfoxyl,heteroaralkylsulfoxyl, alkenylsulfoxyl, alkynylsulfoxyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio,heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl, formyloxy,acyloxy, formylthio, acylthio, amine, alkylamine, arylamine,heteroarylamine, aralkylamine, heteroaralkylamine, alkenylamine,alkynylamine, formylamine, acylamine, carboxyl, alkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl,heteroaralkyloxycarbonyl, amido, alkylaminecarbonyl, arylaminecarbonyl,heteroarylaminecarbonyl, aralkylaminecarbonyl, andheteroaralkylaminecarbonyl; R⁵ is independently for each occurrencehydrogen or lower alkyl; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and m is 1,2, 3, or
 4. 51-59. (canceled)
 60. The method of claim 46, wherein R is Hor alkyl.
 61. The method of claim 46, wherein R is


62. The method of claim 46, wherein the compound is


63. The method of claim 46, further comprising co-administering atherapeutically effective amount of a statin.
 64. The method of claim63, wherein the statin is selected from the group consisting ofatorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,pitavastatin, pravastatin, rosuvastatin and simvastatin.
 65. The methodof claim 47, wherein R is H or alkyl.
 66. The method of claim 47,wherein R is


67. The method of claim 47, wherein the compound is


68. The method of claim 47, further comprising co-administering atherapeutically effective amount of a statin.
 69. The method of claim68, wherein the statin is selected from the group consisting ofatorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,pitavastatin, pravastatin, rosuvastatin and simvastatin.
 70. The methodof claim 48, wherein R is H or alkyl.
 71. The method of claim 48,wherein R is


72. The method of claim 48, wherein the compound is


73. The method of claim 48, further comprising co-administering atherapeutically effective amount of a statin.
 74. The method of claim73, wherein the statin is selected from the group consisting ofatorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,pitavastatin, pravastatin, rosuvastatin and simvastatin.
 75. The methodof claim 49, wherein R is H or alkyl.
 76. The method of claim 49,wherein R is


77. The method of claim 49, wherein the compound is


78. The method of claim 49, further comprising co-administering atherapeutically effective amount of a statin.
 79. The method of claim78, wherein the statin is selected from the group consisting ofatorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,pitavastatin, pravastatin, rosuvastatin and simvastatin.
 80. The methodof claim 50, wherein R is H or alkyl.
 81. The method of claim 50,wherein R is


82. The method of claim 50, wherein the compound is


83. The method of claim 50, further comprising co-administering atherapeutically effective amount of a statin.
 84. The method of claim83, wherein the statin is selected from the group consisting ofatorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,pitavastatin, pravastatin, rosuvastatin and simvastatin.